Methods for the Preparation of Injectable Depot Compositions

ABSTRACT

Injectable depot compositions comprising a biocompatible polymer which is a polymer or copolymer based on lactic acid and/or lactic acid plus glycolic acid having a monomer ratio of lactic to glycolic acid in the range from 48:52 to 100:0, a water-miscible solvent having a dipole moment of about 3.7-4.5 D and a dielectric constant of between 30 and 50, and a drug, were found suitable for forming in-situ biodegradable implants which can evoke therapeutic drug plasma levels from the first day and for at least 14 days.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

The present application claims the benefit of and is a continuation ofapplication Ser. No. 16/253,486 filed Jan. 22, 2019, which is acontinuation-in-part of application Ser. No. 16/032,270, filed Jul. 11,2018 now U.S. Pat. No. 10,195,138 issued Feb. 5, 2019, which is acontinuation-in-part of application Ser. No. 13/690,707 filed Nov. 30,2012, now U.S. Pat. No. 10,058,504 issued Aug. 28, 2018, which is acontinuation-in-part of PCT/EP2011/059001, filed May 31, 2011, whichclaims the benefit of EP 10382153.4 filed May 31, 2010, and saidapplication Ser. No. 16/253,486 is a continuation-in-part of applicationSer. No. 16/220,201, filed Dec. 14, 2018 now U.S. Pat. No. 10,463,607issued Nov. 5, 2019, which is a continuation-in-part of U.S. Ser. No.15/944,894 filed Apr. 4, 2018, now U.S. Pat. No. 10,182,982 issued Jan.22, 2019, which is a divisional of U.S. Ser. No. 13/690,647 filed Nov.30, 2012, now U.S. Pat. No. 10,085,936 issued Oct. 2, 2018, which is acontinuation-in-part of PCT/EP2011/059000 filed May 31, 2011, whichclaims the benefit of EP 10382154.2 filed May 31, 2010, the entiredisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to implantable compositions that formextended release drug-delivery devices comprising certain drugs.Specifically, the present invention is related to injectablecompositions that form biodegradable implants in-situ afteradministration to a subject.

BACKGROUND OF THE INVENTION

Sustained-release delivery devices are usually a very satisfactoryadministration method for certain drugs, in particular (but not limitedto) drugs for patients in need of a treatment for diseases such asschizophrenia. Some treatments for disorders usually involve daily oraltablets or solutions. However, one of the intrinsic problems of thesetreatments is the dissociation (non-compliance) of some schizophrenicpatients from the treatment, especially when therapy requires dailyadministration. Non-compliance leads to irregular or inconstanttreatments and favors the appearance of psychotic crisis or episodes.Moreover, oral tablet therapy gives rise to high fluctuations in theplasma levels (measured as the difference between Cmax and Cmin) inpatients, therefore usually affecting the patient's mood. On thecontrary, administration of sustained-release delivery devices shouldprovide adequate drug delivery to a patient for extended periods of timewith just one dose and without the need of caregivers to pay attentionto a daily medication, thereby providing more homogeneous plasma levelsin the patient.

One of the most common ways to administer certain drugs presently isthrough the use of depot injections. Depot injections allow carefulcontrol of drug usage (as opposed to orally administered drugs) andensure regular contact between the caregivers' team and the patient,where overall treatment efficacy and/or side effects may be identified.Furthermore, it is easy to identify defaulters (non-compliant patients)and prepare interventions. However, in situ forming implants currentlydescribed in the state of the art cannot properly control drug releasefrom the implant and fail to provide therapeutic plasma levelssufficient for a bi-weekly administration protocol while exhibitingreasonable differences between maximum and minimum plasmaconcentrations.

For example, the long-acting injectable risperidone formulation,Risperdal Consta®, is the first depot atypical antipsychotic drug in themarket. It is an intramuscular risperidone-containing PLGA microparticleformulation, and it is intended to deliver therapeutic levels ofrisperidone suitable for bi-weekly administration. However, due to theinherent lag phase of most microparticle-based products, the patient isrequired to supplement the first weeks with daily doses of oralrisperidone after first administration. Approximately three weeks aftera single intramuscular injection of Risperdal Consta® and concurrentdaily doses of oral risperidone, the microspheres release sufficientrisperidone in the systemic circulation that the patient can discontinuesupplementation with daily doses of the oral therapy. However, thisperiod of oral supplementation could be a risk factor of non-compliance.Also, the presence in the body of two doses at the same time couldpresent a potential risk of adverse events, such as irregularformulation behavior and toxicity.

The compositions and devices of the invention, on the contrary, canevoke therapeutic drug plasma levels from the first day and for at least14 days, avoiding the need of supplementary oral daily therapy from theadministration moment. These compositions can also reduce thedifferences between Cmax and Cmin as observed with daily-administeredoral tablets and subsequently may reduce variations in the patient mood.In addition, they can also cover a period within administrations that isat least as long as the period covered by currently marketedextended-release risperidone formulations.

A biodegradable copolymer poly(DL-lactide-co-glycolide) matrix has beenused in medical products, such as sutures described in U.S. Pat. No.3,636,956 by Schneider, surgical clips and staples described in U.S.Pat. No. 4,523,591 by Kaplan et al., and drug delivery systems describedin U.S. Pat. No. 3,773,919 by Boswell et al. However, most of theexisting formulations using these biodegradable polymers requiremanufacturing of an implantable device in solid form prior to theadministration into the body, which device is then inserted through anincision or is suspended in a vehicle and then injected. In suchinstances, the drug is incorporated into the polymer and the mixture isshaped into a certain form such as a cylinder, disc, or fibre forimplantation. With such solid implants, the drug delivery system has tobe inserted into the body through an incision. These incisions aresometimes larger than desired by the medical profession and occasionallylead to a reluctance of the patients to accept such an implant or drugdelivery system.

U.S. Pat. No. 8,221,778 to Siegel et al. (corresponding to WO2005/070332) discloses an implant containing risperidone (10-60% wt) andPLGA (90-40% wt) having a lactic acid to glycolic acid ratio of 50:50 to100:0. These implants are not formed in situ.

Injectable biodegradable polymeric matrix implants based on lactic acid,glycolic acid and/or their copolymers for sustained release have alreadybeen described in the art. U.S. Pat. No. 5,620,700 issued to Berggrendescribes a bioerodible oligomer or polymer material containing drug forlocal application into a diseased tissue pocket such as a periodontalpocket. However, the material requires heating to high temperatures tobecome sufficiently flowable to allow the injection, so that hardeningof the material after cooling to the body temperature conforms theimplant.

U.S. Pat. No. 6,143,314 to Chandrashekar discloses an injectablecomposition that forms an implant in situ. The composition is made ofdrug, organic solvent and a PLGA/PEG block copolymer.

U.S. Pat. No. 6,673,767 issued to Brodbeck describes procedures to forin situ formation of biodegradable implants by using biocompatiblepolymers and biocompatible low water-miscible solvents. A viscouspolymeric solution containing the drug, that upon injection releases thedrug in a controlled manner, can be obtained through the use of lowwater-soluble solvents. Solvents with low water-solubility (less than 7%miscibility in water) are used as a method to reduce the release of thedrug in aqueous mediums, allowing initial drug releases of 10% or lowerduring the first 24 hours. However, in our experience, the use ofwater-immiscible and/or low water-miscible solvents cannotsatisfactorily control the initial in vivo release of risperidone duringthe first 24 hours. For example, the use of benzyl alcohol, a solventspecifically disclosed in U.S. Pat. No. 6,673,767, causes very highplasma levels of risperidone in the first 3 days and then the plasmalevels decrease to very low levels in 7 days.

U.S. Pat. No. 6,331,311 issued to Brodbeck also discloses injectabledepot compositions comprising a biocompatible polymer such as PLGA, asolvent such as N-methyl-2-pyrrolidone and a beneficial agent such as adrug, further comprising an emulsifying agent such as polyols. However,the compositions disclosed do not perform satisfactorily when thebeneficial agent is risperidone because the use of a two-phasecomposition with emulsifying agents accelerates implant hydration andincreases effective releasing surface area, impairing the control on theinitial burst release and originating a fast decrease in drug releasefrom the first days to the following ones. For example, a comparatorcomposition was prepared according to the '311 Patent. A containercontaining risperidone (150 mg), PLGA (300 mg, having an inherentviscosity of 0.32 dl/g and irradiated by β-irradiation to a dose of 25KGy) and NMP (700 mg) was prepared. Another container containingpolyvinyl alcohol in water (1 ml of a 2% wt/v). The contents of thecontainers were mixed, then the mixture was transferred to a syringe andinjected intramuscularly (an amount equivalent to 2.5 mg risperidone)into the gluteus of New Zealand White rabbits (n=3). More than 70% ofthe total AUC of active moiety was released within the first 5 daysafter the injection. Such a formulation is unable to provide therapeuticplasma levels of risperidone for a period of at least two weeks.

U.S. Pat. No. 4,938,763, issued to Dunn et al., discloses a method foran injectable in situ forming implant. A biodegradable polymer orcopolymer dissolved in a water-miscible solvent with a biologicallyactive agent either is dissolved or dispersed within the polymericsolution. Once the polymeric solution is exposed to body fluids, thesolvent diffuses and the polymer solidifies thereby entrapping the drugwithin the polymer matrix. Even though Dunn et al. discloses the use ofwater miscible solvents for obtaining in situ forming polymericimplants, it discloses a number of polymers and solvents and evenproportions between the different ingredients that do not produce asatisfactory implant with the appropriate release characteristics,particularly when the implant contains risperidone as active principle.For example, a comparator composition was prepared according to the '763Patent. A container containing risperidone (50 mg) and PLGA (784 mg,monomer ratio of lactic acid to glycolic acid monomer of 75:25, andhaving an inherent viscosity of 0.20 dl/g) was prepared. Anothercontainer containing NMP (1666 mg) was prepared. The contents of thecontainers were mixed. Then the mixture was transferred to a syringe anda portion (1250 mg, corresponding to 25 mg of risperidone) was injectedinto an aqueous liquid to determine its in vitro release profile. Morethan 50% of the risperidone was released within the first 2 days. Such aformulation is unable to provide therapeutic plasma levels ofrisperidone for a period of at least two weeks.

Another way to avoid surgery to administer these drugs is the injectionof small-sized polymeric particles, microspheres or microparticlescontaining the respective drug. U.S. Pat. Nos. 4,389,330 and 4,530,840describe a method for the preparation of biodegradable microparticles.U.S. Pat. Nos. 5,688,801 and 6,803,055 disclose microencapsulation of1,2-benzazoles into polymeric particles to achieve a drug release overextended periods of time in the treatment of mental disorders. Thesemicroparticles require re-suspension into aqueous solvents prior to theinjection. These formulations do not form a single (nonparticulate)solid implant.

U.S. Pat. No. 5,770,231 describes a method for producing biodegradablemicroparticles for sustained release of risperidone and9-hydroxy-risperidone by dissolving the drug within an organic phase.However, the use of organic solvents that are able to dissolve therisperidone mostly or completely gives rise to very high initial plasmalevels of risperidone due to the diffusion of the drug along with thediffusion of the solvent.

U.S. Pat. No. 7,118,763 describes two methods of making multi-phasesustained-release microparticle formulations based on the combination ofdifferent particle sizes or microparticles exhibiting different releaseprofiles. The combination of two different release profiles allows therelease of the drug for periods longer than two weeks. However, inpractice this combination requires a mixture of particles from at leasttwo different batches, involving the multiplication of end-productspecifications and increasing batch-to-batch variability. In addition,although microparticle formulations can be administered by injection,they cannot always satisfy the demand for a biodegradable implantbecause they sometimes present difficulties in the large-scaleproduction. Moreover, in case of any medical complication afterinjection, they are much more difficult to remove from the body thanimplantable compositions such as those of the invention, which form asingle body.

The art also discloses sustained-release delivery devices comprising adrug, PLGA as polymer and a water-miscible solvent such asn-methyl-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO). However, inpractice the experiments disclosed nearly in every case use NMP assolvent (WO 2004081196, WO 2001035929, WO 2008153611) or need differentadditives to control the initial burst (WO 2000024374, WO 2002038185,WO2008100576).

The compositions already described in the state of the art do notprovide implants adequate for extended periods of treatment, such aschronic treatment compositions, kits and devices. In summary, therestill exists a need of compositions and devices for sustained-releaseddelivery systems providing a controlled, constant release of the drugfrom the very first day, avoiding irregular initial bursts, and showingcontrolled release profile during prolonged periods of time.

SUMMARY OF THE INVENTION

The present invention seeks to overcome one or more of the disadvantagesof known depot formulations. Contrary to known injectable depotcompositions, the compositions of the invention provide an easier methodfor the production of a single unit implantable device allowing constantand effective plasma levels during a period comprising from the firstday up to at least 14 days. The compositions of the invention areinjected as a liquid or semisolid formulation that precipitates bysolvent diffusion after injection into a subject and forms a single (notmultiparticulate) solid implant at an injection site. The compositionsof the present invention provide an easier method for the production ofan implant or single unit implantable device allowing constant andeffective plasma levels during a dosing period comprising from the firstday up to at least 14 days after administration, while avoidingirregular initial burst release of the drug. The compositions of thepresent invention exhibit satisfactory initial and continuous releaseprofiles using DMSO as solvent and without the need of any additionaladditive to control the initial burst of the composition. By usingN-methylpyrrolidone or DMSO as the solvent, both of which have highwater solubility, the implant provides a smaller initial plasma level ofdrug than other injectable formulations and therefore provides a bettercontrol of the release of the drug during the first 5 days after theinjection.

The compositions of the invention provide therapeutic drug plasma levelsfrom the first day up to at least 14 days after implantation, therebyavoiding the need for supplementary oral daily therapy from within oneday of the time of administration. These compositions can also reducethe fluctuations between Cmax and Cmin, especially as compared to thoseobserved with daily administration of oral tablets. In addition, theycan also cover a dosing period that is at least as long as the dosingperiods covered by other known injectable extended-release formulations.

Some of the key points where the compositions of the invention showimprovements over the state of the art include:

-   -   Stability, by using a solid product for reconstitution previous        to injection;    -   Pharmacokinetic profile:        -   Onset: The compositions of the invention provide therapeutic            plasma levels from the first day after administration,            avoiding the 2-3 weeks lag time that the currently marketed            long-term product shows.        -   Duration: The compositions of the invention may allow an            increase in the interval between administrations, meaning an            increase in the dosing period, as compared to currently            marketed long-term product.    -   Plasma levels: The compositions of the invention provide more        evenly sustained plasma levels, and with lower differences        between Cmax and Cmin than the currently marketed long-term        product.

The present inventors have identified that the initial burst release ofthe drug can be satisfactorily controlled during at least 2 weeks bycontrolling at least one of the following parameters of the composition,either alone or in combination:

-   -   the viscosity of the polymeric solution;    -   the inherent or intrinsic viscosity of the polymer; and    -   the water solubility of the active ingredient.

It should be noted that there was little recognition, if any, in the artthat the above-enumerated variables would be result effective in termsof their impact upon the initial release of drug after implantation orafter placement in an aqueous fluid. By adequately controlling at leastsome of these result effective variables, release of drug from theimplant during at least the first two weeks can be precisely controlled,allowing “satisfactorily controlled” release profiles from the veryfirst day until at least 14 days, and achieving in most cases dosingperiods of more than 21 days and up to six months following a singleadministration.

The composition and kit, used to prepare the composition, are providedwith a solid polymer or copolymer that is soluble in a solvent, which isnon-toxic and water miscible, to form a liquid polymer solution, inwhich the drug is included. When the implantable compositions areexposed to body fluids or water, the solvent diffuses away from thepolymer-drug mixture and water diffuses into the mixture where itcoagulates the polymer thereby trapping or encapsulating the drug withinthe polymeric matrix as the composition solidifies into a single implantat the injection site. The release of drug follows the generalcharacteristics for diffusion or dissolution of a drug from within apolymeric matrix. Drug is also released by polymer erosion/degradation.The drug (active ingredient) forms a suspension or dispersion within abiodegradable and biocompatible polymeric solution to form an injectablecomposition that can be administered by way of a syringe (or pump) and aneedle. The composition solidifies inside the body by solvent diffusion,thereby forming the single implant at the site of injection.

One aspect of the invention provides an injectable composition asdescribed and/or exemplified herein. The compositions of the inventioncomprise at least a polymer matrix, a solvent for the polymer and adrug, wherein the composition is defined by certain selected ranges andratios of at least one of the following parameters, either alone or incombination:

-   -   The water solubility of the drug;    -   The intrinsic viscosity of the polymer; and/or    -   The viscosity of the polymeric solution or injectable        composition.

The invention provides an injectable composition comprising:

-   -   a. a drug (and/or a metabolite and/or a prodrug thereof) having        a water solubility of less than or about 2 mg/ml;    -   b. a biocompatible polymer, which is a polymer or        copolymer-based on lactic acid or a copolymer of lactic acid and        glycolic acid having a monomer ratio of lactic to glycolic acid        in the range from 48:52 to 100:0, wherein the polymer (or        copolymer) has an inherent viscosity in the range of 0.20-0.50        dl/g; and    -   c. a water-miscible solvent having a dipole moment of about        3.7-4.5 D and a dielectric constant of between 30 and 50,        thereby providing the injectable composition having a viscosity        in the range of about 0.50 and 4.0 Pa·s.

Embodiments of the invention include those wherein: a) the drug isselected from the group consisting of fentanyl, olanzapine, risperidoneand letrozole; b) the solvent is selected from the group consisting ofDMSO and NMP; c) the polymer is selected from the group consisting ofpoly(lactic acid), poly(lactic acid-co-glycolic acid) copolymer and acombination thereof; d) the monomer ratio of the poly(lacticacid-co-glycolic acid) copolymer is in the range of about 48:52 to100:0, and the copolymer has an inherent or intrinsic viscosity in therange of about 0.16-0.60 dl/g measured in chloroform at 25° C. and at aconcentration of 0.1% wt; e) the polymer has an inherent or intrinsicviscosity in the range of about 0.20-0.50 dl/g or 0.25-0.48 dl/g,measured in chloroform at 25° C. and 0.1% concentration wt/v; f) theconcentration of polymer in the injectable composition is in the rangeof about 20 to about 50%, about 25 to about 40%, or about 30 to about40%, expressed as the percentage of polymer weight based on total weightof injectable composition; g) the viscosity of the injectablecomposition is in the range of about 0.5-7.0 Pa·s, about 0.5-4.0 Pa·s,or about 0.7-4.0 Pa·s; h) the drug (or metabolite or prodrug thereof)has a particle size where not more than 10% of the total volume of theparticles is less than the range 0.1-10 μm, 0.5-10 μm or 1-10 μm, notmore than the 10% of the total volume of particles is greater than therange 225-1000 μm, 225-700 μm or 225-400 μm, respectively, and the d0.5of the size distribution is in the range of about 10-1000 μm, 20-700 μmor 40-200 μm, respectively, i) the ratio of solvent to polymer is in therange of about 4:1 to about 1:1, about 3:1 to about 1.2:1, or about 2:1to about 1.4:1; k) the composition is injectable by hand with a syringethrough a 18-22 gauge or 20-21 gauge needle; and/or l) the polymericsolution excluding drug has a viscosity in the range of about 0.5 to 3.0Pa·s or 0.7 to 3.0 Pa·s.

Embodiments of the invention include those wherein: a) the drug issoluble, partially soluble or insoluble in the solvent; b) thesolubility of the drug in the solvent is about 90 mg/ml or less, about65 mg/ml or less, or about 10 mg/ml or less; c) a minor portion, a majorportion or none of the drug is present in particulate form in theinjectable composition; d) the particle size distribution of the drugexpressed as volume is as follows: d0.9 about 150-400 μm, d0.5 about40-200 μm and d0.1 about 10-60 μm; e) the mass ratio of solvent to drugis in the range of about 10:1 to about 1.5:1 f) the concentration ofdrug in the injectable composition is in the range of about 4% to about40% wt or about 4% to about 25%, expressed as the percentage of the drugwith respect to the total composition weight; g) the drug is present asparticles, is partially dissolved in or is completely dissolved in theinjectable composition prior to administration; h) the mass ratio of theamount of polymeric solution (polymer+solvent) to the amount of drug inthe injectable composition ranges from about 24:1 to about 1.5:1 orabout 15:1 to about 3:1.

Another aspect of the invention provides a pharmaceutical kit suitablefor in situ formation of a biodegradable non-particulate solid implantin a subject in need thereof, the kit comprising: a first containercomprising a drug, and/or a metabolite and/or a prodrug thereof, havinga water solubility less than or about 2 mg/ml and a biocompatiblepolymer having an inherent viscosity in the range of about 0.20-0.50dl/g or about 0.20-0.48 dl/g; and a second container comprising awater-miscible solvent in which the biocompatible polymer is soluble,the solvent having a dipole moment of about 3.7-4.5 D and a dielectricconstant of between 30 and 50, whereby mixing of the contents of thefirst container with the contents of the second container affectsformation of an injectable composition as described herein having aviscosity in the range of about 0.50 and 4.0 Pa·s. In some embodiments,the containers are syringes and the mixing of the contents of the firstand second containers may be performed by direct or indirect connectionfollowed by moving the plungers of the syringes forwards and backwards.

Embodiments of the invention include those wherein: a) drug is presentin solid form in the container prior to mixing with the solvent; b) drugis present in particulate form or as a lyophilisate in the containerprior to mixing with the solvent; c) the kit further comprises analkaline agent; d) the mole ratio of alkaline agent to drug ranges from1/3 to 5/2; e) the solvent, polymeric solution, drug and/or injectablecomposition is sterilized prior to administration; and/or f) the kitfurther comprises an alkaline agent in either or both containers.

Another aspect of the invention provides a method for the preparation ofan injectable depot composition as described and/or exemplified herein.In some embodiments, the method comprises:

-   -   a. mixing a biocompatible polymer, which is a polymer or        copolymer-based on lactic acid and/or lactic acid plus glycolic        acid having a monomer ratio of lactic to glycolic acid in the        range from 48:52 to 100:0, wherein the polymer has an inherent        viscosity in the range of 0.20-0.50 dl/g, with a drug, and/or a        metabolite or a prodrug thereof in any combination, having a        water solubility less than or about 2 mg/ml, wherein the drug is        selected from the group consisting of fentanyl, olanzapine,        risperidone and letrozole, to provide a mixture; and    -   b. mixing the mixture obtained in step a) with a water-miscible        solvent having a dipole moment of about 3.7-4.5 D and a        dielectric constant of between 30 and 50 to form the injectable        composition, wherein the viscosity of the polymeric solution is        in the range of about 0.50 and 3.0 Pa·s. or the viscosity of the        injectable composition is in the range of about 0.50 and 4.0        Pa·s.

Some embodiments of the invention include those wherein: a) the polymerand/or drug is exposed to an amount of beta-irradiation sufficient, e.g.5 to 25 KGy, to sterilize the polymer and/or drug; b) the polymer isexposed to an amount of beta-irradiation sufficient, e.g. 10-25 KGy, toreduce the molecular weight, and thereby the intrinsic viscosity, of thepolymer; and/or c) sterilizing the solvent by filtering it through afiltration medium have a nominal pore size of 0.22 microns or less.

Another aspect of the invention provides a method for the treatment of adisease, disorder or condition that is therapeutically responsive to adrug, the method comprising administering an amount of injectablecomposition, as defined herein, to a subject in need thereof, whereinthe amount of injectable composition comprises a dose of drug sufficientto continuously provide therapeutically effective plasma levels of drugin the subject throughout a dosing period of at least 14 days or atleast four weeks beginning from the day of administration.

Embodiments of the invention include those wherein: a) the compositionis administered every two weeks, every three weeks, every four weeks orevery five weeks during a treatment period; b) the composition providesa therapeutic plasma level of drug or other form thereof from within 24hours after administration to at least 14 days or at least four weeksafter administration; c) the plasma level of active moiety(risperidone+9-OH risperidone) ranges from about 5 to about 150 ng/mland preferably from about 10 to about 100 ng/ml in the steady stateduring a dosing period; d) the implant provides an active moiety(risperidone+9-OH risperidone) plasma level within the range of about 5to about 80 ng/ml when about 116 to about 700 mg, respectively, of thecomposition comprising about 25 to about 150 mg, respectively, ofrisperidone are administered via injection; e) the injectablecomposition is exposed to an aqueous fluid thereby forming a solid bodywhich is then administered to a subject in need thereof; f) theinjectable composition is formed within one month, within three weeks,within two weeks, within one week, within three days, within one day,within less than one day, within 18 hours, within 12 hours, within 6hours, within 1 hour, within 15 minutes or within 5 minutes prior toadministration to a subject; g) the injectable composition is warmed orcooled prior to administration to a subject; h) the polymer, solventpolymer solution and/or drug is sterilized prior to administration; i)sterilization comprises sterilization of the drug or polymer by exposureto beta-irradiation in the range 5-25 KGy; j) sterilization comprisessterilization of the polymer solution by filtration through a filtrationmedium having a nominal pore size of 0.22 microns or less; k) thecomposition is administered intramuscularly, intraperitoneally,intrathecally, intravaginally, subcutaneously, intracranially orintracerebrally; l) the plasma level of fentanyl ranges from about 0.2to about 5 ng/ml and preferably from about 0.5 to about 2.5 ng/ml in thesteady state during a dosing period; m) the plasma level of olanzapineranges from about 5 to about 120 ng/ml and preferably from about 10 toabout 80 ng/ml in the steady state during a dosing period; n) the plasmalevels of letrozole should be sufficient to provide an in vivosuppression on serum estrogens (E1 and E2) of at least about 50% (E2,estradiol) and 70% (E1, estrone) and preferably of at least about 60%(E1) and 80% (E2) in the steady state during a dosing period. Someindividual subjects may, on an equivalent dose basis, exhibit plasmaconcentrations outside the ranges specified herein for reasons such aspoor health, advanced age, compromised metabolism, renal failure,disease, etc. Even so, a majority of subjects in a patient population towhich the injectable implant is administered will exhibit plasmaconcentrations with those specified herein.

The specification discloses one or more embodiments that incorporatefeatures of this invention. The scope of the present invention is notlimited solely to the disclosed embodiments. The invention includes allcombinations and sub-combinations of the various aspects and embodimentsdisclosed herein. These and other aspects of this invention will beapparent upon reference to the following detailed description, examples,claims and attached figures.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate one or more embodiments of the presentinvention and, together with the description, further serve to explainthe principles of the present invention and to enable a person skill inthe pertinent art to make and use the invention. The following drawingsare given by way of illustration only, and thus are not intended tolimit the complete scope of the present invention.

FIG. 1 depicts the release profile of Rivastigmine and Bemiparin fromimplants prepared according to Comparative Example 1. Results areexpressed as % drug released from implants as a function of time.

FIG. 2 depicts the plasma levels profile of Rivastigmine in New Zealandrabbits provided by implants prepared according to ComparativeExample 1. Results are expressed as the concentration of Rivastigmine asa function of time.

FIG. 3 depicts the release profile of Fentanyl and Olanzapine fromimplants prepared according to Example 1. Results are expressed as %drug released from implants as a function of time.

FIG. 4 depicts the release profile of Risperidone and Letrozole fromimplants prepared according to Example 1. Results are expressed as %drug released from implants as a function of time.

FIG. 5 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 1. Resultsare expressed as the sum of the concentration of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 6 depicts the plasma level profile of Letrozole in New Zealandrabbits provided by implants prepared according to Example 1. Resultsare expressed as the concentration of Letrozole as a function of time.

FIG. 7 depicts the plasma level profile of Fentanyl in New Zealandrabbits provided by implants prepared according to Example 2. Resultsare expressed as the concentration of Fentanyl as a function of time.

FIG. 8 depicts the plasma level profile of Olanzapine in New Zealandrabbits provided by implants prepared according to Example 2. Resultsare expressed as the concentration of Olanzapine as a function of time.

FIG. 9 depicts the release profile of Fentanyl from implants preparedaccording to Example 3. Results are expressed as % Fentanyl releasedfrom implants as a function of time.

FIG. 10 depicts the plasma level profile of Fentanyl in New Zealandrabbits provided by implants prepared according to Example 3. Resultsare expressed as the concentration of Fentanyl as a function of time.

FIG. 11 depicts the plasma level profile of Fentanyl in New Zealandrabbits provided by implants prepared according to Example 3. Resultsare expressed as the concentration of Fentanyl as a function of time.

FIGS. 12 and 13 depict the release profile of Olanzapine from implantsprepared according to Example 4. Results are expressed as % Olanzapinereleased from implants as a function of time.

FIG. 14 depicts the plasma level profile of Olanzapine in New Zealandrabbits provided by implants prepared according to Example 4. Resultsare expressed as the concentration of Olanzapine as a function of time.

FIG. 15 depicts the release profile of Risperidone from implantsprepared according to Example 5. Results are expressed as % Risperidonereleased from implants as a function of time.

FIG. 16 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 5. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 17 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 5. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 18 depicts the release profile of Letrozole from implants preparedaccording to Example 6. Results are expressed as % Letrozole releasedfrom implants as a function of time.

FIG. 19 depicts the plasma level profile of Letrozole in New Zealandrabbits provided by implants prepared according to Example 6. Resultsare expressed as the concentration of Letrozole as a function of time.

FIG. 20 depicts the plasma level profile of Letrozole in New Zealandrabbits provided by implants prepared according to Example 6. Resultsare expressed as the concentration of Letrozole as a function of time.

FIG. 21 depicts the release profile of Fentanyl from implants preparedaccording to Example 7. Results are expressed as % Fentanyl releasedfrom implants as a function of time.

FIG. 22 depicts the plasma level profile of Fentanyl in New Zealandrabbits provided by implants prepared according to Example 7. Resultsare expressed as the concentration of Fentanyl as a function of time.

FIG. 23 depicts the release profile of Olanzapine from implants preparedaccording to Example 8. Results are expressed as % Olanzapine releasedfrom implants as a function of time.

FIG. 24 depicts the release profile of Risperidone from implantsprepared according to Example 9. Results are expressed as % Risperidonereleased from implants as a function of time.

FIG. 25 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 9. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 26 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 9. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 27 depicts the release profile of Letrozole from implants preparedaccording to Example 10. Results are expressed as % Letrozole releasedfrom implants as a function of time.

FIG. 28 depicts the release profile of Letrozole from implants preparedaccording to Example 10. Results are expressed as % Letrozole releasedfrom implants as a function of time.

FIG. 29 depicts the plasma level profile of Letrozole in New Zealandrabbits provided by implants prepared according to Example 10. Resultsare expressed as the concentration of Letrozole as a function of time.

FIG. 30 depicts the plasma level profile of Letrozole in New Zealandrabbits provided by implants prepared according to Example 10. Resultsare expressed as the concentration of Letrozole as a function of time.

FIG. 31 depicts the release profile of Fentanyl and Risperidone fromimplants prepared according to Comparative Examples 2-3. Results areexpressed as % drug released from implants as a function of time.

FIG. 32 depicts the release profile of Olanzapine, Risperidone andLetrozole from implants prepared according to Comparative Examples 2-3.Results are expressed as % drug released from implants as a function oftime.

FIG. 33 depicts the plasma level profile of Fentanyl in New Zealandrabbits provided by implants prepared according to Comparative Examples2-3. Results are expressed as the concentration of Fentanyl as afunction of time.

FIG. 34 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Comparative Examples2-3. Results are expressed as the sum of the concentrations ofRisperidone and its active metabolite 9-hydroxide-risperidone as afunction of time.

FIG. 35 depicts the release profile of Fentanyl from implants preparedaccording to Example 11. Results are expressed as % Fentanyl releasedfrom implants as a function of time.

FIG. 36 depicts the release profile of Risperidone from implantsprepared according to Example 12. Results are expressed as % Risperidonereleased from implants as a function of time.

FIG. 37 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 12. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 38 depicts the release profile of Letrozole from implants preparedaccording to Example 13. Results are expressed as % Letrozole releasedfrom implants as a function of time.

FIG. 39 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 14. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 40 depicts the release profile of Risperidone from implantsprepared according to Example 15. Results are expressed as % Risperidonereleased from implants as a function of time.

FIG. 41 depicts the release profile of Risperidone from implantsprepared according to Example 15. Results are expressed as % Risperidonereleased from implants as a function of time.

FIG. 42 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 15. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 43 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 15. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 44 depicts the release profile of Risperidone from implantsprepared according to Example 16. Results are expressed as % Risperidonereleased from implants as a function of time.

FIG. 45 depicts the plasma level profile of Risperidone in New Zealandrabbits provided by implants prepared according to Example 16. Resultsare expressed as the sum of the concentrations of Risperidone and itsactive metabolite 9-hydroxide-risperidone as a function of time.

FIG. 46 depicts the plasma level profile of Risperidone in Beagle dogsprovided by implants prepared according to Example 16. Results areexpressed as the sum of the concentrations of Risperidone and its activemetabolite 9-hydroxide-risperidone as a function of time.

FIGS. 47 and 48. depict exemplary embodiments of syringes suitable foradministering the injectable composition.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and unless otherwise specified, the drug or activeingredient included in the injectable composition can be present in freebase, salt, amorphous, crystalline, anhydrous, hydrate, optically pure,optically enriched or racemic forms thereof. Combinations of thesevarious forms are also within the scope of the invention. A prodrug,metabolite or derivative of the drug can also be included.

As used herein, the term “prodrug” is taken to mean a compound that isadministered in an inactive (or less than fully active) form, and issubsequently converted to an active pharmacological agent through normalmetabolic processes. A prodrug serves as a type of ‘precursor’ to theintended drug, e.g. risperidone, olanzapine, letrozole, fentanyl orother drug.

As used herein, the term “derivative” is taken to mean a compound thatis obtained by chemical modification of a parent compound such that the“derivative” includes within it almost all or all of the chemicalstructure of the parent (or base) compound. A derivative is a compoundthat is formed from a similar compound or a compound that can beimagined to arise from another compound, if one atom is replaced withanother atom or group of atoms. A derivative is a compound derived orobtained from another and containing essential elements of the parentsubstance. A derivative is a chemical compound that may be produced fromanother compound of similar structure in one or more steps.

As used herein, the term “polymeric solution” is taken to mean the fluidcomposition comprising a combination of the solvent and the polymerdissolved therein. In some embodiments, at least 80%, at least 90%, atleast 95%, at least 99% or all of the polymer is dissolved in thesolvent. If not otherwise specified, the viscosity value of thepolymeric solution or the injectable composition is given in Pa·s units.

The salt forms of the drugs listed herein can be obtained commercially.The salt should have a water solubility as specified herein. The saltforms of risperidone can be made according to U.S. Publication No.20040266791, the relevant disclosure of which is hereby incorporated byreference. Suitable fentanyl salts include hydrobromide, hydrochloride,mutate, citrate, succinate, n-oxide, sulfate, malonate, acetate,phosphate dibasic, phosphate monobasic, acetate trihydrate,bi(heplafluorobutyrate), maleate, bi(methylcarbamate),bi(pentafluoropropionate), mesylate; bi(pyridine-3-carboxylate),bi(trifluoroacetate), bitartrate, chlorhydrate, fumarate, and sulfatepentahydrate salts. Suitable olanzapine salts include acid additionsalts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, hydroxymaleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, naphthalene-2-sulfonicacid, and salicylic acid. Suitable letrozole salts include hydrochloridesalts. In some embodiments, the drug, metabolite and/or prodrug ispresent in freebase form.

By “satisfactorily controlled” release profile is meant that the implantwill exhibit an initial release profile that is not too steep (fast),which would otherwise lead to plasma levels that are too high withconcomitant toxic side effects, and an initial release profile that isnot too flat (slow), which would lead to plasma levels that are belowtherapeutic concentrations. An implant exhibiting a satisfactorilycontrolled initial release profile will release 0.5 to 20% wt., 1 to 12%wt. or 2 to 8% wt of its charge of drug within 24 hours after beingplaced in an aqueous environment (liquid or subject). It will release nomore than 20% wt., no more than 12% wt or no more than 8% wt of itscharge of drug within 24 hours after being placed in an aqueousenvironment. It will release at least 0.5% wt., at least 2% wt. or atleast 3% wt of its charge of drug within 24 hours after being placed inan aqueous environment.

The injectable composition comprises at least a polymer, a solvent and adrug, wherein the composition has a viscosity within a specified range,the polymer has an intrinsic viscosity within a specified range, thedrug has a water solubility at or below a maximum specified value, thepolymer has a specified composition, and the solvent has a dipole momentand dielectric constant within specified ranges.

The polymer or polymer matrix is preferably a biocompatible andbiodegradable polymer matrix. In order not to cause any severe damage tothe body following administration, the preferred polymers arebiocompatible, non-toxic for the human body, not carcinogenic, and donot induce significant tissue inflammation. The polymers are preferablybiodegradable in order to allow natural degradation by body processes,so that they are readily disposable and do not accumulate in the body.In selecting the appropriate grade of PLGA copolymer, the time requiredfor degradation of PLGA is related to the monomer ratio used inproduction: the higher the content of glycolide units, the lower thetime required for degradation. In addition, polymers that are end-cappedwith esters (as opposed to the free carboxylic acid) demonstrate longerdegradation half-lives. The preferred polymers are selected fromend-capped terminal carboxylic poly-lactide and poly-glycolic acidcopolymers mixed in a ratio from 48:52 to 100:0, with an inherent orintrinsic viscosity preferably in the range of 0.16-0.60 dl/g, and morepreferably between 0.20-0.50 dl/g as measured in chloroform at 25° C. ata concentration of 0.1% wt/v with a Ubbelohde size 0c glass capillaryviscometer (RESOMER® grades) or as measured in chloroform at 30° C. andat a concentration of 0.5% wt/v with a size 25 Cannon-Fenske glasscapillary viscometer (LAKESHORE MATERIALS™ grades). The concentration ofthe polymeric component in the compositions of the invention ispreferably in the range of about 20-50%, (expressed as the percentage ofpolymer weight based on total polymeric solution component) and morepreferably in the range of about 25 to about 40%. Suitable grades ofPLGA copolymers as described herein (according to molecular weight,intrinsic viscosity and/or molar ratio of lactic acid monomer toglycolic acid monomer) are end-capped (such as with an ester group, e.g.lauryl ester, methyl ester) are available from EVONIK® (Essen, Germany),Boehringer Ingelheim (Ingelheim am Rhein, Germany), ALKERMES (Dublin,Ireland) or SIGMA ALDRICH (ST. Louis, Mo.) and are marketed under thetradenames RESOMER®, LAKESHORE BIOMATERIALS™, or MEDISORB®. As thecomposition of some grades of end-capped PLGA is proprietary, theidentity of the ester end-cap is not publicly available. Nonetheless,the performance properties of the grades of PLGA copolymer describedherein are known and are used to characterize the material.

As used herein, the term intrinsic viscosity or inherent viscosity(η_(inh)) of the polymer is defined as the ratio of the naturallogarithm of the relative viscosity, η_(r), to the mass concentration ofthe polymer, c, i.e.:

η_(inh)=(ln η_(r))/C

and the relative viscosity (η_(r)) is the ratio of the viscosity of thesolution η to the viscosity of the solvent ns, i.e.:

η_(r)=η/η_(s)

If not otherwise specified, the intrinsic viscosity values throughoutthe present specification are to be understood as measured at 25° C. inchloroform at a concentration of 0.1%. The value of intrinsic viscosityis considered in the present specification, as commonly accepted in theart, as an indirect indicator of the polymer molecular weight. In thisway, a reduction in the intrinsic viscosity of a polymer, measured at agiven concentration in a certain solvent, with same monomer compositionand terminal end groups, is an indication of a reduction in the polymermolecular weight (IUPAC. Basic definitions of terms relating topolymers; Pure App. Chem. (1974) 40, 477-491).

Suitable solvents are non-toxic, biocompatible and appropriate forparenteral injection. Solvents susceptible of causing toxicity shouldnot be used for the injection of any material into any living body.Preferably, solvents are biocompatible in order not to cause severetissue irritation or necrosis at the injection site. Therefore, thesolvent is preferably classified as class III, according to ICHGuidelines. For the formation of the in-situ implant, the solvent shouldpreferably diffuse quickly from the polymeric solution towardssurrounding tissues when is exposed to physiological fluids. Solventdiffusion should also lead to the formation of a polymer precipitatethat retains the active ingredient, effectively controlling the releaseof the active ingredient for at least 14 days have been achieved incertain cases up to now. Consequently, the solvent is preferably watermiscible, and more preferably showing certain polarity characteristics.In this term, polarity is considered as a function of three parameters:water miscibility, dipole moment and dielectric constant. The solvent ispreferably a polar aprotic solvent with a high solubility in water,having a dipole moment in the range of 3.7-4.5 D at 25° C., and adielectric constant in the range of 30-50 at 25° C. Suitable solventsinclude DMSO (dimethylsulfoxide), N-methyl-pyrrolidone (NMP) and PEG(poly(ethylene glycol), e.g. MW ˜200 or ˜300). In some embodiments, theinjectable composition comprises a combination or two or three of thesesolvent.

In some embodiments, the drug is completely dissolved, partiallydissolved or completely undissolved in the solvent used to form thepolymeric solution. Solubility of the drug in DMSO is not a criticalparameter, as the composition described can effectively control drugdiffusion when the drug is either dissolved or suspended in solid formin the ready-to-inject liquid composition. In some embodiments, ≤5%,≤10%, ≤20%, ≤30%, ≤40%, ≤50%, ≤60%, ≤70%, ≤80%, ≤90%, ≤95% or ≤99% wt ofthe drug is dissolved in the solvent or polymeric solution to form theinjectable composition. In some embodiments, ≥1%, ≥5%, ≥10%, ≥20%, ≥30%,≥40%, ≥50%, ≥60%, ≥70% or up to about 80% wt. of the drug is dissolvedin the solvent or polymeric solution to form the injectable composition.

The drug is preferably a poorly water-soluble drug with a watersolubility about 2 mg/ml or less at 20° C. The poorly water soluble drugmay be present in any form having the desired water solubility maximum.The advantage of this low solubility is that the initial burst of thedrug when the solvent diffuses into the external aqueous medium,following placement therein, is greatly reduced. Suitable biologicallyactive agents (drugs) include substances capable of producing abiological effect locally or either systemically, and include, forexample, antipsychotics, hormones, vaccines, anti-inflammatory agents,antibacterial agents, antifungal agents, antiviral agents, analgesics,anti-parasitic agents, substances capable of regulating cellular ortissue survival or growth of function, antineoplastic agents, narcoticantagonists, and precursors or prodrugs. In preferred embodiments, thedrug is selected from the group consisting of risperidone, olanzapine,letrozole or fentanyl.

One of the main factors controlling the initial release drug from theimplant is the viscosity of the polymeric solution and injectablecomposition. The viscosity of the polymeric solution is preferably inthe range of about 0.20-7.0 Pa·s, more preferably in the range of about0.7-3.0 Pa·s, and most preferably in the range of about 0.7-2.0 Pa·s.The viscosity can be controlled primarily according to the molecularweight (the intrinsic or inherent viscosity) of the polymer and theconcentration of polymer in the injectable composition.

In some embodiments, the concentration of drug in the injectablecomposition is generally in the range of about 4 and 40% wt or about 4to about 25% wt, expressed as the percentage of the drug with respect tothe total composition weight. More preferably, the drug content isbetween 7 and 35% wt, and most preferably about 13-25% wt with respectto the total composition weight.

The initial release of drug from the implant can be controlled byvarying the drug/polymer mass ratio of the injectable composition. Insome embodiments, this mass ratio, expressed as the percentage of thedrug weight with respect to total weight of the drug plus polymer, is inthe range of about 15-50% weight, more preferably about 25-50% wt, andmost preferably about 33-45% wt.

Yet another factor that may contribute toward controlling the initialrelease of drug from the implant is the drug's particle size. Largeparticles provide a smaller surface area per weight thereby reducing theinitial release (burst) but the release may be then delayed until thebeginning of the degradation of the polymeric matrix. On the other hand,small particles evoke higher burst levels due to increased surface areaand easier drug diffusion from small particles during implant hardening,followed by continuous drug release levels due to the combination of theprocesses of drug diffusion and implant erosion. Consequently, in apreferred embodiment of the invention a wide particle size distribution,combining large and small particle sizes in different ratios, is used inorder to reduce the initial burst and still maintain a suitable constantdrug release by diffusion of smaller particles during the first phase ofrelease and gradual release of drug from the bigger particles while thepolymer degrades, i.e. during the period of time (days to weeks)following the initial burst phase.

The mass ratio of the amount of solvent to the amount of risperidone (mgsolvent/mg risperidone) in the injectable composition ranges may alsocontribute toward controlling the initial release of drug from theimplant. In some embodiments, the mass ratio of the amount of solventand the amount of drug (mg solvent/mg drug) in the injectablecomposition ranges from about 12:1 to about 1.5:1, about 10:1 to about1.5:1 or about 5:1 to about 1.5:1. In some embodiments, this mass ratiois about 4.66:1, as described in the examples below.

The mass ratio of the amount of polymeric solution to the amount of drugin the injectable composition ranges may also contribute towardcontrolling the initial release of drug from the implant. In someembodiments, the mass ratio ranges from about 24:1 to about 1.5:1, about12:1 to about 2:1, about 7:1 to about 2.5:1 or about 6.7:1 to 3:1. Insome embodiments, this mass ratio is about 6.66:1, as described in theexamples below.

Optionally, an alkaline agent with low water solubility such as lowerthan 0.02 mg/ml can be included within the polymer matrix. The alkalineagent can be present in a molar ratio of from about 3/1 to 2/5,expressed as the molar ratio of drug to alkaline agent. Preferredalkaline agents are alkaline or alkaline-earth hydroxides, such asmagnesium hydroxide or aluminum hydroxide. Due to the limited watersolubility of the alkaline agent, the d0,5 of the particle sizedistribution thereof, e.g. of the magnesium hydroxide, is preferablybelow 10 microns.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a drug, or a metabolite or prodrug thereof, having a water        solubility of less than or about 2 mg/ml; and    -   b. a polymeric solution comprising a biodegradable,        biocompatible polymer, which is a polymer or copolymer-based on        lactic acid or a copolymer of lactic acid and glycolic acid        having a monomer ratio of lactic to glycolic acid in the range        from 48:52 to 100:0, wherein the polymer (or copolymer) has an        inherent viscosity in the range of 0.20-0.50 dl/g, and a        water-miscible solvent having a dipole moment of about 3.7-4.5 D        and a dielectric constant of between 30 and 50, thereby        providing the injectable composition having a viscosity in the        range of about 0.50 and 4.0 Pa·s.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. a drug, or a metabolite or prodrug thereof, having a water        solubility of less than or about 2 mg/ml;    -   b. an alkaline agent having a water solubility of about 0.02        mg/ml or less, wherein the alkaline agent is present in molar        excess over the drug or wherein the drug is present in molar        excess over the alkaline agent; and    -   c. a polymeric solution comprising a biodegradable,        biocompatible polymer, which is a polymer or copolymer-based on        lactic acid or a copolymer of lactic acid and glycolic acid        having a monomer ratio of lactic to glycolic acid in the range        from 48:52 to 100:0, wherein the polymer (or copolymer) has an        inherent viscosity in the range of 0.20-0.50 dl/g, and a        water-miscible solvent having a dipole moment of about 3.7-4.5 D        and a dielectric constant of between 30 and 50, thereby        providing the injectable composition having a viscosity in the        range of about 0.50 and 4.0 Pa·s.; wherein    -   d. the concentration of drug in the injectable composition is in        the range of about 4% to about 40% wt, expressed as the        percentage of the drug with respect to the total composition        weight; and    -   e. the composition provides a satisfactorily controlled release        profile throughout a dosing period of at least 21 days after        administration.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   -   a. A drug selected from the group consisting of Olanzapine,        risperidone, paliperidone, fentanyl or letrozole;    -   b. an alkaline agent selected from the group consisting of        magnesium hydroxide and aluminum hydroxide, wherein the alkaline        agent is present in molar excess over the drug or wherein the        drug is present in molar excess over the alkaline agent; and    -   c. a polymeric solution comprising a biodegradable,        biocompatible PLGA copolymer of lactic acid and glycolic acid        having a monomer ratio of lactic to glycolic acid in the range        from 48:52 to 100:0, wherein the copolymer has an inherent        viscosity in the range of 0.20-0.50 dl/g, and dimethylsulfoxide,        thereby providing the injectable composition having a viscosity        in the range of about 0.50 and 4.0 Pa·s.; wherein    -   d. the concentration of drug in the injectable composition is in        the range of about 4% to about 40% wt, expressed as the        percentage of the drug with respect to the total composition        weight; and    -   e. the composition provides a satisfactorily controlled release        profile throughout a dosing period of at least 21 days after        administration.

Another aspect of the invention provides a kit comprising: a firstcontainer containing a polymer in solid form, drug and, optionally,Mg(OH)₂ in predetermined amounts; and a second container containing awater-miscible solvent. When required, the contents of both containersare combined, for example through a connector or by using male-femalesyringes, and mixed each other so that the compositions according to theinvention are reconstituted, for example by moving forwards andbackwards the plungers of the syringes. The polymer is preferablyprovided in freeze-dried (lyophilized) form. Each container isindependently selected at each occurrence from a syringe, vial, deviceand cartridge. Each container is independently at each occurrencedisposable or not disposable. Illustrative preferred embodiments of thecontainers are depicted in FIG. 47 (syringes connected through aconnector device) and in FIG. 48 (syringes connected through a directthread)

In some embodiments, the injectable depot composition is sterile as afinished product. The biocompatible polymer can be sterilized prior toits aseptic filling process, preferably by an aseptic filling process bybeta-irradiation in the range 5-25 KGy or it can be sterilized afterbeing dissolved in a solvent to form a polymeric solution followed byfiltration of the polymeric solution through a filter with a 0.22 μmpore size or less. Alternatively, the drug and/or the biocompatiblepolymer of the composition may be subjected to terminal sterilizationprocesses, preferably by beta-irradiation in the range 5-25 KGy.

The polymer can be sterilized by β-irradiation. Example 15 describes anexemplary process for sterilization of the composition. The polymer andrisperidone were mixed and subjected to β-irradiation in the range 10-25KGy. Exposure to radiation caused the polymer to degrade therebyresulting in a polymer with reduced molecular weight and a correspondingpolymer solution with reduced viscosity. In some embodiments, theinvention provides a process for preparing an injectable composition asdescribed herein, the process comprising: a) subjecting a PLGA polymerto a sufficient amount of β-irradiation to degrade at least a portion ofthe polymer thereby reducing its molecular weight; and b) dissolving thepolymer in a solvent to form a polymeric solution having a desiredviscosity. In some embodiments, a mixture of drug and PLGA polymer areexposed to beta-irradiation prior to addition of the solvent, whichwould result in formation of a sterilized injectable composition of theinvention.

Embodiments of the invention include those wherein: a) the molecularweight of the polymer is greater before irradiation than it is afterirradiation; b) the molecular weight of the polymer is greater than 10KDa before irradiation; c) the molecular weight of the polymer is in therange of 10-60 KDa, 10-52 KDa or 10-43 KDa after irradiation; d) theviscosity of a polymeric solution containing polymer that has not beenirradiated is greater than about 0.5 Pa·s; e) the viscosity of apolymeric solution containing polymer that has been irradiated is in therange of 0.5-7.0 Pa·s, 0.5-3.0 Pa·s or 0.7 to 2.0 Pa·s.; and/or f) thesufficient amount of radiation is at least 10, at least 15, at least 20or at least 25 KGy.

In another preferred embodiment, in the injectable depot composition atleast the drug and/or the biocompatible polymer of the composition havebeen submitted to terminal sterilization processes, preferably byirradiation in the range of 5-25 KGy.

The injectable composition is used to treat a disorder, disease orcondition that is therapeutically responsive to a drug. The inventioncomprises administering to a subject in need thereof an amount ofinjectable composition sufficient to provide therapeutic plasma levelsof drug in the subject during the period of at least 1 to 14, at least 2to 14 or at least 3 to 14 days after administration (the dosing period).The dosing period can exceed two weeks and can be up to three weeks,four weeks, five weeks, six weeks, two months, three months, fourmonths, five months or six months. The method can comprise one or moreor plural dosing periods as part of an overall treatment period.

As used herein, the term “dosing period” refers to the period of days orweeks as measured from the initial day after administration to at least14 days after administration. During the dosing period, the implant willprovide therapeutic plasma levels of drug for at least 11 days, at least12 days, at least 13 days, at least 14 days, at least 21 days, at least28 days, at least 31 days or at least 36 days. The dosing period canexceed two weeks and can be up to three weeks, four weeks, five weeks,six weeks, two months, three months, four months, five months or sixmonths. A dosing period can end after expiration of a predeterminednumber of days or after the plasma level of risperidone drops belowtherapeutic levels.

As used herein, a “treatment period” refers to the weeks, months oryears during which implants of the invention are administered to asubject. A treatment period generally comprises plural dosing periods.Dosing periods can occur sequentially or in an overlapping manner duringa treatment period. A treatment period will vary according to the drugadministered and the disease, disorder or condition being treated andaccording to the dosage and administration protocols approved by theU.S.F.D.A. for each drug. For example, a first dose of injectablecomposition is administered and a second dose of injectable compositioncan be administered within one to two weeks following administration ofthe first dose, such that each dose will have its own correspondingdosing period, and the dosing periods would overlap.

The injectable composition can be administered to a subject in one ormore injection sites on the same day and still be considered as beingpart of the same dosing period. For example, part of a dose can beadministered to a first injection site and another part of the same dosecan be administered to another injection site. A single-body implantwill form at each injection site. Such a mode of administration within asame day is considered to be administration of a single dose with adosing period.

Alternatively, administration can be modified such that there is onepoint of needle entry into the subject but more than one injection sitebelow the skin, which can be achieved by making a first penetration intothe skin and muscle and administering a portion of a dose, thenpartially withdrawing and redirecting the needle into another section ofmuscle, while maintaining the tip of the needle beneath the skin, andthen injecting another portion of the dose into this other section ofmuscle. Such a mode of administration is still considered to beadministration of a single dose within a dosing period.

The plasma concentration profile during the dosing period can exhibitone, two, or more maxima and one, two or more minima. An initial maximumcan be caused by dissolution of risperidone during the initial day(s) ofthe dosing period followed by a slowing of the release thereof andanother maximum can be caused by increased rate of release during theremaining days of the dosing period. Embodiments of the inventioninclude those wherein: a) the plasma profile exhibits a maximum duringthe initial one to three days or one to two days of the dosing period;b) the plasma profile exhibits a maximum during the latter 11 to 13 daysor 12 to 14 days of the dosing period; c) the plasma profile exhibits amaximum during the initial days of the dosing period and a maximumduring the remaining days of the dosing period; or d) the plasma profileis substantially level (within ±20%, ±15%, ±10% or ±5% of the average ormean) during the dosing period.

The implant of the invention can provide substantially improved plasmalevels of drug during the initial one to three days after administrationwhen compared to another injectable formulation (not according to theinvention) containing the same drug when administered on an equivalentdose basis.

In humans, the average plasma concentration of risperidone can rangefrom about 3-200, about 5-80, or about 10-60 ng/ml when an amount ofinjectable composition equivalent to a dose of about 25-150, about37.5-125, or about 50-100 mg of risperidone is administered. The averageCmin during the dosing period is in the range of about 1-80, 5-50, orabout 5-40 ng/ml when an amount of injectable composition equivalent toa dose of about 25-150, about 37.5-125, or about 50-100 mg,respectively, of risperidone is administered. The average Cmax duringthe dosing period is in the range of about 8-300, 10-150, or 10-120ng/ml when an amount of injectable composition equivalent to a dose of25-150, 37.5-125, or 50-100 mg, respectively, of risperidone isadministered. Some individual subjects may, on an equivalent dose basis,exhibit plasma concentrations outside the ranges specified herein forreasons such as poor health, advanced age, compromised metabolism, renalfailure, disease, etc. Even so, a majority of subjects in a patientpopulation to which the injectable implant is administered will exhibitplasma concentrations with those specified herein.

As used herein, whenever the plasma concentration of a drug ismentioned, such plasma concentration includes within it the sum total ofthe plasma concentration of the drug and its active metabolite(s). Forexample, whenever the plasma concentration of risperidone is mentioned,such plasma concentration includes within it the sum total of the plasmaconcentrations of risperidone and its active metabolite(s), such as9-OH-risperidone (paliperidone).

As used herein the term, “initial burst” or “initial release” refers tothe addition of the plasma levels of drug plus active metabolite(s),which addition is also called “the active moiety” throughout the presentspecification, from the moment of injection/administration of theinjectable composition to a subject in need thereof until completion ofthe third day after the administration. For example, the drug can berisperidone and its metabolite can be paliperidone. In some embodiments,the initial period of release is within three days, within two days,within one day or within twelve hours after administration.

The following examples illustrate the invention and should not beconsidered as defining the full scope thereof.

Comparative Example 1: Implantable Composition Including a Drug Having aWater Solubility >2 mg/mL (Example not According to the Invention)

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer lactic/ Inherent Polymer glycolic Viscosity ComponentAmount (mg) Solution Drug ratio (dL/g) Solvent Drug Polymer SolventViscosity (Pa · s) Rivastigmine 50:50 0.40 DMSO 50 100 233.2 1.12 baseRivastigmine 50:50 0.40 DMSO 50 100 233.2 1.12 tartrate Bemiparin 50:500.40 DMSO 50 200 466.6 1.12

The implantable formulations were prepared by completely dissolving thepolymer in the solvent, thereby forming the so-called “polymericsolution”, and subsequently adding the drug to the polymeric solution.

In Vitro Release Profile:

The drug released from each formulation of this example was evaluatedaccording to the following procedure: The amount of formulationcorresponding to 25 mg of drug was injected from prefilled syringes intoflasks having a pre-warmed release medium by using a 21G needle. Therelease-medium was 250 ml phosphate buffer, pH=7.4. The flasks were thenplaced into an oven at 37° C. and kept under horizontal shaking at 50rpm. At previously scheduled time points (2 h, 1 d, and periodically upto 14 days), 5 ml of release medium was collected and replaced withfresh buffer and the amount of drug present in the sample was determinedby UV spectrophotometry for rivastigmine base and tartrate, andnephelometry in the case of bemiparin. The profile of drug released fromthe implants of this example is shown in FIG. 1. The results areexpressed as % drug released from implants as a function of time.

As depicted in FIG. 1, the release of rivastigmine tartrate andbemiparin during the first 24 hours is completely uncontrollable, beinghigher than 70% of the injected amount. In the case of rivastigminebase, the release was substantially lower, however it was also quitehigh during the first 24 hours, close to 15% of the injected amount andclose to 35% in the first 48 hours and 80% after 5 days, thereforeproducing a high drug release by diffusion process and a consequentincapacity of the formulation to control the release of the drugs.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The rivastigmine formulations of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 30 mg rivastigmine andthe formulation was placed intramuscularly in the left hind leg using asyringe with a 20G needle. The total number of rabbits per formulationwas 3. After injection, plasma levels were obtained at 0, 4 h, 1 d, 2 d,4 d and 7 d.

The kinetics of the plasma levels corresponding to the rivastigmine wasevaluated. The profile of the plasma levels of the rivastigmine is shownin FIG. 2. As it can be observed in this Figure, the injection of anamount of formulation equivalent to 30 mg rivastigmine to New ZealandWhite rabbits resulted in very high initial plasma levels followed by arapid decrease, with no significant plasma levels from day 2 onwards.

These results are in accordance within vitro findings, whichdemonstrates the rather poor control on the initial drug releaseachieved when drugs with solubility >2 mg/ml are used in theformulations of the invention.

Example 1: Implantable Composition Including a Drug with WaterSolubility <2 mg/mL

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer Inherent Solution lactic/glycolic ViscosityComponent Amount (mg) Viscosity Drug ratio (dL/g) Solvent Drug PolymerSolvent (Pa · s) Fentanyl 50:50 0.40 DMSO 25 150 350 1.12 Olanzapine50:50 0.40 DMSO 25 50 116.6 1.12 Risperidone (in vitro profile) 50:500.40 DMSO 25 50 116.6 1.12 Risperidone (in vivo profile) 50:50 0.40 DMSO25 100 233.2 1.12 Letrozole (in vitro profile) 50:50 0.43 DMSO 25 50116.6 1.62 Letrozole (in vivo profile) 50:50 0.43 DMSO 25 30 70 1.62

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from each formulation of this example was evaluatedaccording to the following procedure depending on the formulated drug:The amount of formulation corresponding to 9, 10, 25 or 3 mg offentanyl, olanzapine, risperidone or letrozole was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was phosphate buffer pH=7.4 (100ml for fentanyl and 250 ml for the remaining drugs). The flasks werethen placed into an oven at 37° C. and kept under horizontal shaking at50 rpm. At previously scheduled time points (2 h, 1 d, and periodicallyup to 21, 42 or 58 days), 5 ml of release medium was collected andreplaced with fresh buffer and the amount of drug present in the samplewas determined by UV spectrophotometry (fentanyl, olanzapine,risperidone) or HPLC-FLD (letrozole). The profile of drug released fromthe implants of this example is shown in FIG. 3 (fentanyl, olanzapine)and FIG. 4 (risperidone, letrozole). The results are expressed as % drugreleased from implants as a function of time.

As depicted in FIGS. 3 and 4, the release of the four drugs wascontrolled to a different extent depending on the drug, but in all casesa certain control was obtained at least during 21 days. None of thedrugs showed a high initial burst release, such release being less than10% during the first 24 hours and less than 15% during the first 3 daysin all the cases.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The risperidone and letrozole formulations of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone or5.4 mg letrozole, and the formulation was placed intramuscularly in theleft hind leg using a syringe with a 20G needle. The total number ofrabbits per composition was 3. After injection, plasma levels wereobtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10, 14 d and periodicallyup to 35 d and 56 d, respectively.

The kinetics of the drug plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels of therisperidone (active moiety, corresponding to risperidone plus itspharmacologically equivalent metabolite 9-OH-risperidone) and letrozoleis shown in FIG. 5 and FIG. 6, respectively. As it can be observed inthese Figures, the injection of an amount of formulation equivalent to15 mg risperidone or 5.4 mg letrozole to New Zealand White rabbitsresulted in controlled initial plasma levels, conferring to thecompositions a duration of at least 21 and 49 days, respectively, withconstant levels until the drug is completely released when plasma levelsdecline.

Example 2: Implantable Composition Including a Drug with WaterSolubility <2 mg/mL (Continuation)

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer lactic/glycolic Inherent Component Amount (mg)Solution Drug ratio Viscosity (dL/g) Solvent Drug Polymer SolventViscosity (Pa · s) Fentanyl 50:50 0.40 DMSO 25 100 250 6.77 Olanzapine50:50 0.40 DMSO 50 50 100 1.85In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The formulations of this example were intramuscularly injected to NewZealand White rabbits weighing an average of 3 kg. The amount injectedcorresponded to a dose of 4.2 mg fentanyl or 46.2 mg olanzapine, and thecomposition was intramuscularly placed in the left hind leg using asyringe with a 20G needle. The total number of rabbits per formulationwas 3. After injection, plasma levels were obtained at 0, 4 h, 1 d, 2 d,and periodically up to 14 d and 36 d, respectively.

The kinetics of the drug plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels of thefentanyl and olanzapine is shown in FIG. 7 and FIG. 8, respectively. Asit can be observed in these Figures, the injection of an amount ofcomposition equivalent to 4.2 mg fentanyl or 46.2 mg olanzapine to NewZealand White rabbits resulted in controlled initial plasma levels,conferring to the compositions a duration of at least 14 and 28 days,respectively, with constant levels, particularly in the case ofolanzapine, until the drug is almost completely released when plasmalevels decline.

The results of this example, together with Example 1, show that drugshaving a water solubility lower than 2 mg/mL can be satisfactorily usedin the implantable formulations of the invention.

Example 3: Different Inherent Viscosities of the Polymer for the DrugFentanyl

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Inherent Solution Polymer lactic/ Viscosity ComponentAmount (mg) Viscosity Formulation Drug glycolic ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Fentanyl 50:50 0.40 DMSO 25 75 175 1.12B Fentanyl 50:50 0.40 DMSO 25 100 150 6.77 C Fentanyl 75:25 0.20 DMSO 25200 300 0.43 D Fentanyl 75:25 0.20 DMSO 25 125 125 1.95

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from formulations A and C of this example wasevaluated according to the following procedure: The amount offormulation corresponding to 9 mg of fentanyl was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was 100 ml phosphate bufferpH=7.4. The flasks were then placed into an oven at 37° C. and keptunder horizontal shaking at 50 rpm. At previously scheduled time points(2 h, 1 d, and periodically up to 20 d), 5 ml of release medium wascollected and replaced with fresh buffer and the amount of fentanylpresent in the sample was determined by UV spectrophotometry. Theprofile of fentanyl released from the implants of this example is shownin FIG. 9. The results are expressed as % drug released from theimplants as a function of time.

As depicted in FIG. 9, the release of the fentanyl is controlled betterwhen 0.40 dL/g inherent viscosity polymer (composition A) is usedinstead of 0.20 dL/g (composition C). The higher inherent viscositypolymer is capable of controlling the initial burst during first 24hours, such burst being lower than 10% in the case of 0.40 dL/g, whereasit is above 10% in the case of 0.20 dL/g polymer. After 3 days, in thecase of 0.20 dL/g inherent viscosity the release is close to 30%, andclose to 60% after 10 days, whereas in the case of 0.40 dL/g viscositythe release is below 15% and 30% after 3 and 10 days respectively.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The fentanyl formulations of this example were injected intramuscularlyto New Zealand White rabbits weighing an average of 3 kg. The amountinjected corresponded to a dose of 4.2 mg fentanyl, and the formulationwas placed intramuscularly in the left hind leg using a syringe with a20G needle. The total number of rabbits per composition was 3. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 4 d, 7 d, 10d and 14 d.

The kinetics of fentanyl plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels of fentanylis shown in FIGS. 10 and 11. As depicted in these figures, the injectionof an amount of formulation equivalent to 4.2 mg fentanyl to New ZealandWhite rabbits resulted in better controlled initial plasma levels (first3 days) when a polymer with an inherent viscosity of 0.40 dL/g(compositions A and B) instead of 0.20 dL/g (compositions C and D) wasused.

Example 4: Different Inherent Viscosities of the Polymer for the DrugOlanzapine

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Olanzapine 50:50 0.43 DMSO 25 50 116.61.62 B Olanzapine 50:50 0.43 DMSO 25 33.3 66.7 3.16 C Olanzapine 75:250.20 DMSO 25 66.6 100 0.43 D Olanzapine 75:25 0.38 DMSO 25 50 116.6 0.66E Olanzapine 100:0  0.30 DMSO 25 25 50 0.46

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from composition A, C, D and E of this example wasevaluated according to the following procedure. The amount offormulation corresponding to 10 mg of olanzapine was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was 250 ml phosphate bufferpH=7.4. The flasks were then placed into an oven at 37° C. and keptunder horizontal shaking at 50 rpm. At previously scheduled time points(2 h, 1 d, and periodically up to 21 d or 49 d), 5 ml of release mediumwas collected and replaced with fresh buffer and the amount ofolanzapine present in the sample was determined by UV spectrophotometry.The profile of olanzapine released from the implants of this example isshown in FIGS. 12 and 13. The results are expressed as % drug releasedfrom implants as a function of time.

As depicted in FIG. 12, the release of the olanzapine is notsatisfactorily controlled when a 0.20 dL/g inherent viscosityformulation (formulation C) is used instead of 0.43 dL/g (formulationA), the latter showing an overall faster drug release in spite of thefact that the former formulation comprises a 75:25 lactic/glycolicpolymer with a degradation time slower than a 50:50 one, probably due toa high diffusion process resulting in the shown incapability to retainthe drug. On the other hand, the formulation with 0.43 dL/g inherentviscosity showed a controlled drug release until the polymer started todegrade (around 10 days). FIG. 13 shows how polymers with inherentviscosity of 0.30 and 0.38 dL/g are also capable to satisfactorilycontrol the initial olanzapine release until at least the time when thepolymer begins to degrade, namely around 21 days for 75:25lactic/glycolic polymer (formulation D) and longer than 49 days for100:0 lactic/glycolic polymer (formulation E).

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The olanzapine formulations B and D of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 46.3 mg olanzapine,and the composition was placed intramuscularly in the left hind legusing a syringe with a 20G needle. The total number of rabbits percomposition was 3. After injection, plasma levels were obtained at 0, 4h, 1 d, 2 d, 4 d, 7 d, 10 d and periodically up to 56 days.

The kinetics of olanzapine plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels ofolanzapine is shown in FIG. 14. As depicted in this figure, theinjection of an amount of formulation equivalent to 46.2 mg olanzapineto New Zealand White rabbits resulted in constant and controlled initialplasma levels (first 3 days) when a polymer with an inherent viscosityof 0.38 and 0.43 dL/g was used, with duration periods of 49 and 28 daysrespectively.

Example 5: Different Inherent Viscosities of the Polymer for the DrugRisperidone

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Risperidone 50:50 0.22 DMSO 25 116.3215.9 0.32 B Risperidone 50:50 0.22 DMSO 25 166.1 166.1 3.18 CRisperidone 50:50 0.40 DMSO 25 100 233.3 1.12 D Risperidone 75:25 0.20DMSO 25 100 150 0.43 E Risperidone 75:25 0.38 DMSO 25 50 116.6 0.66 FRisperidone 100:0  0.30 DMSO 25 50 116.6 0.26

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from formulations A, C, and D of this example wasevaluated according to the following procedure: The amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was 250 ml phosphate bufferpH=7.4. The flasks were then placed into an oven at 37° C. and keptunder horizontal shaking at 50 rpm. At previously scheduled time points(2 h, 1 d, and periodically up to 49 d), 5 ml of release medium wascollected and replaced with fresh buffer and the amount of risperidonepresent in the sample was determined by UV spectrophotometry. Theprofile of risperidone released from the implants of this example isshown in FIG. 15. The results are expressed as % drug released fromimplants as a function of time.

As depicted in FIG. 15, the release of the risperidone is notsatisfactorily controlled when polymers having 0.20 and 0.22 dL/ginherent viscosity values (Formulations D and A, respectively) were usedinstead of 0.40 dL/g (Formulation C), the latter formulations showingfaster drug releases in spite of the fact that the 75:25 lactic/glycolicpolymer (composition D) has a degradation time slower than a 50:50polymer. These low inherent viscosity polymers demonstrate theirinability for an adequate control of the drug release, probably due tothe fact that they evoke high drug diffusion processes. Once again, 0.40dL/g inherent viscosity polymers show a well-controlled drug releaseuntil the polymer starts to degrade (around 14 days).

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The risperidone compositions B, C, D, E and F of this example wereinjected intramuscularly to New Zealand White rabbits weighing anaverage of 3 kg. The amount injected corresponded to a dose of 15 mgrisperidone, and the composition was placed intramuscularly in the lefthind leg using a syringe with a 20G needle. The total number of rabbitsper composition was 3. After injection, plasma levels were obtained at0, 4 h, 1 d, 2 d, 4 d, 7 d, 10 d and periodically up to 28 days.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIGS. 16 and 17. Theresults are expressed as the sum of the risperidone plus9-OH-risperidone concentrations (ng/ml) as a function of time, since thetherapeutic activity of 9-OH-risperidone is substantially equivalent tothat of risperidone. As depicted in these figures, the injection of anamount of composition equivalent to 15 mg risperidone to New ZealandWhite rabbits resulted in poorly controlled plasma levels when a lowinherent viscosity polymer, 0.20 and 0.22 dL/g was used (Formulations Dand B, respectively). Composition D is incapable to satisfactorilycontrol the initial drug release, eliciting high initial plasma levelsand a subsequent fast decrease, whereas composition B cannot avoid anuncontrollable release, showing a profile with two plasma peaks. On theother hand, polymers with higher inherent viscosity (0.30-0.40 dL/g)induced moderate initial plasma levels during first 24 hours followed bysustained levels during at least 28 days.

Example 6: Different Inherent Viscosities of the Polymer for the DrugLetrozole

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Letrozole 50:50 0.43 DMSO 25 63.9 149.11.62 B Letrozole 75:25 0.20 DMSO 25 85.2 127.8 0.43 C Letrozole 75:250.38 DMSO 25 63.9 149.1 0.66 D Letrozole 100:0  0.30 DMSO 25 85.2 127.81.20

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug release from composition A, Band C of this example wasevaluated according to the following procedure: The amount offormulation corresponding to 3 mg of letrozole was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was 250 ml phosphate bufferpH=7.4. The flasks were then placed into an oven at 37° C. and keptunder horizontal shaking at 50 rpm. At previously scheduled time points(2 h, 1 d, and periodically up to 94 d depending on the profile), 5 mlof release medium was collected and replaced with fresh buffer and theamount of letrozole present in the sample was determined by HPLC-FLD.The profile of letrozole released from the implants of this example isshown in FIG. 18. The results are expressed as % drug released fromimplants as a function of time.

As depicted in FIG. 18, the release of the letrozole is not controlledwhen a 0.20 dL/g inherent viscosity polymer (Formulation B) was usedinstead of 0.38 or 0.43 dL/g (Formulations C and A, respectively), theformer showing a faster drug release probably due to high drug diffusionprocesses. On the other hand, 0.38 and 0.43 dL/g inherent viscositypolymers showed controlled drug release for at least 63 days or more(Formulation C).

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The letrozole compositions A, C and D of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of letrozole of 5.4 mg(composition A and C) or 16.2 mg (composition D), and the compositionwas placed intramuscularly in the left hind leg using a syringe with a20G needle. The total number of rabbits per composition was 3. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 4 d, 7 d, 10d and periodically up to 56 days.

The kinetics of letrozole plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels of letrozoleis shown in FIG. 19 and FIG. 20. As depicted in FIG. 19, the injectionof an amount of formulation equivalent to 5.4 mg letrozole to NewZealand White rabbits resulted in controlled initial plasma levels(first 3 days) with a duration period of at least 56 days when polymershaving an inherent viscosity of 0.38-0.43 dL/g were used. Hence, aninherent viscosity of 0.30 dL/g (FIG. 20) resulted in an adequatecontrol of the initial plasma levels followed by constant plasma levelsfor at least 35 days.

Example 7: Different Viscosities of the Polymeric Solution for the DrugFentanyl

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Fentanyl 50:50 0.40 DMSO 25 55 220 0.18B Fentanyl 50:50 0.40 DMSO 25 75 175 1.12 C Fentanyl 50:50 0.40 DMSO 25100 150 6.77

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from Formulations A and B of this example wasevaluated according to the following procedure: The amount offormulation corresponding to 9 mg of fentanyl was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was 100 ml phosphate bufferpH=7.4. The flasks were then placed into an oven at 37° C. and keptunder horizontal shaking at 50 rpm. At previously scheduled time points(2 h, 1 d, and periodically up to 20 d), 5 ml of release medium wascollected and replaced with fresh buffer and the amount of fentanylpresent in the sample was determined by UV spectrophotometry. Theprofile of fentanyl released from the implants of this example is shownin FIG. 21. The results are expressed as % drug released from implantsas a function of time.

As depicted in FIG. 21, the release of the fentanyl it is bettercontrolled when a polymer solution having a viscosity of 1.12 Pa·s isused instead of 0.18 Pa·s. The low viscosity polymer solution(Formulation A) fails to control the release of fentanyl, allowing adiffusion of 30% of the drug during the first 24 hours, whereas thehigher viscosity polymer solution (composition B) allowed a controlledrelease for 21 days.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The fentanyl Formulations Band C of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 4.2 mg fentanyl, andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. The total number of rabbits per compositionwas 3. After injection, plasma levels were obtained at 0, 4 h, 1 d, 2 d,4 d, 7 d, 10 d and 14 d.

The kinetics of fentanyl plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels of fentanylis shown in FIG. 22. As it can be observed in this Figure, the injectionof an amount of composition equivalent to 4.2 mg fentanyl to New ZealandWhite rabbits resulted in controlled initial plasma levels (first 3days) when the viscosity of polymer solution of composition is in therange 1.12-6.77 Pa·s, and a duration of around 14 days.

Example 8: Different Viscosities of the Polymeric Solution for the DrugOlanzapine

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymeric lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Olanzapine 50:50 0.43 DMSO 25 33.3 66.73.16 B Olanzapine 75:25 0.38 DMSO 25 50 116.6 0.66 C Olanzapine 100:0 0.30 DMSO 25 25 50 0.46

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from the formulations of this example was evaluatedaccording to the following procedure: The amount of formulationcorresponding to 10 mg of olanzapine was injected from prefilledsyringes into flasks having a pre-warmed release medium by using a 21Gneedle. The release medium was 250 ml phosphate buffer pH=7.4. Theflasks were then placed into an oven at 37° C. and kept under horizontalshaking at 50 rpm. At previously scheduled time points (2 h, 1 d, andperiodically up to 21 d or 49 d), 5 ml of release medium was collectedand replaced with fresh buffer and the amount of olanzapine present inthe sample was determined by UV spectrophotometry. The profile ofolanzapine released from the implants of this example is shown in FIG.23. The results are expressed as % drug released from implants as afunction of time.

As depicted in FIG. 23, the release of the olanzapine is satisfactorilycontrolled at the initial moment and later on when polymers havingdifferent lactic/glycolic ratios (from 50:50 to 100:0) were used informulations with a viscosity of the polymeric solution in the range of0.46-3.16 Pa·s.

Example 9: Different Viscosities of the Polymeric Solution for the DrugRisperidone

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymeric lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Risperidone 50:50 0.40 DMSO 25 33.3 3000.04 B Risperidone 50:50 0.40 DMSO 25 66.7 266.6 0.18 C Risperidone50:50 0.40 DMSO 25 100 233.3 1.12 D Risperidone 50:50 0.40 DMSO 25 133.3200 6.77 E Risperidone 75:25 0.38 DMSO 25 50 116.6 0.66 F Risperidone100:0  0.30 DMSO 25 50 116.6 0.26

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from compositions A, B, C, and D of this example wasevaluated according to the following procedure: The amount offormulation corresponding to 25 mg of risperidone was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was 250 ml phosphate bufferpH=7.4. The flasks were then placed into an oven at 37° C. and keptunder horizontal shaking at 50 rpm. At previously scheduled time points(2 h, 1 d, and periodically up to 49 d), 5 ml of release medium wascollected and replaced with fresh buffer and the amount of risperidonepresent in the sample was determined by UV spectrophotometry. Theprofile of risperidone released from the implants of this example isshown in FIG. 24. The results are expressed as % drug released fromimplants as a function of time.

As depicted in FIG. 24, the release of the risperidone it is absolutelynot controlled when the viscosity of the polymer solution was 0.04 Pa·s,and not satisfactorily controlled in the case of 0.18 Pa·s, where aninitial drug release higher than 15% during first 24 hours, and close to25% during first 3 days, was observed. On the other hand, higher polymersolution viscosities, in this example 1.12 and 6.77 Pa·s, resulted in asuitable control of the drug release, allowing prolonged release timesfor at least 35 days.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The risperidone Formulations C, D, E and F of this example wereintramuscularly injected to New Zealand White rabbits weighing anaverage of 3 kg. The amount injected corresponded to a dose of 15 mgrisperidone, and the composition was intramuscularly placed in the lefthind leg using a syringe with a 20G needle. The total number of rabbitsper composition was 3. After injection, plasma levels were obtained at0, 4 h, 1 d, 2 d, 5 d, 7 d, 10 d and periodically up to 35 days.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIGS. 25 and 26. Theresults are expressed as the sum of the risperidone plus9-OH-risperidone concentrations (ng/ml) as a function of time, since thetherapeutic activity of 9-OH-risperidone is substantially equivalent tothat of risperidone. As it can be observed in these Figures, theinjection of an amount of composition equivalent to 15 mg risperidone toNew Zealand White rabbits resulted in satisfactorily controlled plasmalevels in all cases when polymer solution viscosities in the range0.26-6.77 Pa·s where used, thereby providing therapeutic plasma levelsafter 4 hours, and sustained plasma levels from the 3rd day until atleast 21 days.

Example 10: Different Viscosities of the Polymeric Solution for the DrugLetrozole

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymeric lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Letrozole 50:50 0.43 DMSO 25 63.9 149.11.62 B Letrozole 75:25 0.38 DMSO 25 63.9 149.1 0.66 C Letrozole 75:250.38 DMSO 25 74.6 138.4 1.45 D Letrozole 100:0  0.30 DMSO 25 63.9 149.10.26 E Letrozole 100:0  0.30 DMSO 25 85.2 127.8 1.20

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from Formulations A, B, D and E of this example wasevaluated according to the following procedure: The amount offormulation corresponding to 3 mg of letrozole was injected fromprefilled syringes into flasks having a pre-warmed release medium byusing a 21G needle. The release medium was 250 ml phosphate bufferpH=7.4. The flasks were then placed into an oven at 37° C. and keptunder horizontal shaking at 50 rpm. At previously scheduled time points(2 h, 1 d, and periodically depending on the obtained profile), 5 ml ofrelease medium was collected and replaced with fresh buffer and theamount of letrozole present in the sample was determined by HPLC-FLD.The profile of letrozole released from the implants of this example isshown in FIG. 27 and FIG. 28. The results are expressed as % drugreleased from implants as a function of time.

As depicted in these figures, the release of the letrozole issatisfactorily controlled in all cases where polymeric solutions havinga viscosity in the range 0.26-1.62 Pa·s were used. All the formulationsshowed an initial release below 10% during first day. As FIG. 27 shows,both 50:50 (Composition A) and 75:25 (Composition B) lactic/glycolicpolymer satisfactorily control the release of letrozole, although therelease rate was logically slower (with a consequent longer durationperiod) for the 75:25 polymer. A polymer with a 100:0 lactic/glycolicratio (FIG. 28, Compositions D and E) also resulted in a satisfactoryinitial and sustained control.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The letrozole compositions A, C and E of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of letrozole of 5.4 mg(Formulation A) or 16.2 mg (Formulations C and E), and the compositionwas placed intramuscularly in the left hind leg using a syringe with a20G needle. The total number of rabbits per composition was 3. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d and periodically up to 56 days.

The kinetics of letrozole plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels of letrozoleis shown in FIG. 29 and FIG. 30. As depicted in FIG. 29, the injectionof an amount of composition equivalent to 16.2 mg letrozole to NewZealand White rabbits resulted in controlled initial plasma levels(first 3 days) with a duration period of at least 21 days when theviscosity of the polymer solution was 1.20-1.45 Pa·s, and using 75:25 or100:0 lactic/glycolic polymers. Also, the injection of an amount ofcomposition equivalent to 5.4 mg letrozole with a composition involvinga polymer solution viscosity of 1.62 Pa·s (FIG. 30) resulted insatisfactorily controlled initial plasma levels followed by constantplasma levels for at least 42 days using a 50:50 lactic/glycolicpolymer.

Comparative Examples 2-3: Implantable Formulations Including a Low WaterMiscible Solvent (Example not According to the Invention)

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymeric lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Fentanyl 75:25 0.20 BB 25 150 350 1.25 BFentanyl 75:25 0.20 BA 25 200 300 1.05 C Fentanyl 75:25 0.20 AA 25 250250 1.58 D Olanzapine 75:25 0.38 BB 25 50 116.6 6.45 E Risperidone 75:250.20 BB 25 100 233.3 1.25 F Risperidone 75:25 0.20 BA 25 133.3 200 1.05G Letrozole 75:25 0.38 BB 25 50 116.6 6.45 BB: benzyl benzoate; BA:benzyl alcohol; AA: acetic acid

In Vitro Release Profile:

The drug release from compositions B, D, E, F, and G of this example wasevaluated according to the following procedure, variable depending onthe formulated drug: The amount of formulation corresponding to 9, 10,25 or 3 mg of fentanyl, olanzapine, risperidone or letrozole wasinjected from prefilled syringes into flasks having a pre-warmed releasemedium by using a 21G needle. The release medium was phosphate bufferpH=7.4 (100 ml for fentanyl and 250 ml for the remaining drugs). Theflasks were then placed into an oven at 37° C. and kept under horizontalshaking at 50 rpm. At previously scheduled time points (2 h, 1 d, andperiodically up to 28 days, depending of each compositions), 5 ml ofrelease medium was collected and replaced with fresh buffer and theamount of drug present in the sample was determined by UVspectrophotometry (fentanyl, olanzapine, risperidone) or HPLC-FLD(letrozole). The profile of drug released from the implants of thisexample is shown in FIG. 31 and FIG. 32. The results are expressed as %drug released from implants as a function of time.

As depicted in these figures, low water miscible solvents such as benzylbenzoate and benzyl alcohol resulted unsuitable for their use ininjectable long lasting implantable systems according to the invention,since their drug release profile is too fast for the desired targets,and resulted uncontrollable, as it can be observed based on the highinitial drug release during first days.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The fentanyl and risperidone formulations of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 4.2 mg fentanyl or 15mg risperidone, and the composition was placed intramuscularly in theleft hind leg using a syringe with a 20G needle. The total number ofrabbits per composition was 3. After injection, plasma levels wereobtained at 0, 4 h, 1 d, 2 d, and periodically up to 14 d and 28 d,respectively.

The kinetics of the drug plasma levels corresponding to the eachcomposition was evaluated. The profile of the plasma levels of thefentanyl and risperidone (active moiety, corresponding to risperidoneplus its pharmacologically equivalent metabolite 9-OH-risperidone) isshown in FIG. 33 and FIG. 34, respectively.

As depicted in FIG. 33, fentanyl implantable compositions based in lowwater miscible solvents as benzyl benzoate, benzyl alcohol and aceticacid evoke huge initial plasma levels during first day, followed by afast release with almost no levels from the 2nd day. In the case ofrisperidone (FIG. 34), the use of same low water miscible solventsresults in very high initial plasma levels (first 4 hours) and, as forfentanyl, followed by a very fast decrease to low plasma levels,therefore failing to achieve the objective of sustained plasma levelsduring at least 14 days.

Example 11: Use of Different Water-Soluble Solvents Having DifferentPolarities for Drug Fentanyl

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymeric lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Fentanyl 50:50 0.40 NMP 25 150 350 1.08B Fentanyl 50:50 0.40 DMSO 25 150 350 1.12

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from the formulations of this example was evaluatedaccording to the following procedure: The amount of formulationcorresponding to 9 mg of fentanyl was injected from prefilled syringesinto flasks having a pre-warmed release medium by using a 21G needle.The release medium was 100 ml phosphate buffer pH=7.4. The flasks werethen placed into an oven at 37° C. and kept under horizontal shaking at50 rpm. At previously scheduled time points (2 h, 1 d, and periodicallyup to 20 d), 5 ml of release medium was collected and replaced withfresh buffer and the amount of fentanyl present in the sample wasdetermined by UV spectrophotometry. The profile of fentanyl releasedfrom the implants of this example is shown in FIG. 35. The results areexpressed as % drug released from the implants as a function of time.

As depicted in FIG. 35, the release of the fentanyl is well controlledand sustained for at least 21 days when the solvent used, probably dueto its high water miscibility, shows certain polarity characteristicssuch as large dipole moment (3.7-4.5 D) and high dielectric constant(30-50) as those used in this example.

Example 12: Use of Different Water-Soluble Solvents Having DifferentPolarities for the Drug Risperidone

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Risperidone 50:50 0.40 Dioxane 25 100233.3 2.50 B Risperidone 50:50 0.40 NMP 25 100 233.3 1.08 C Risperidone50:50 0.40 DMSO 25 100 233.3 1.12

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from the formulations of this example was evaluatedaccording to the following procedure: The amount of formulationcorresponding to 25 mg of risperidone was injected from prefilledsyringes into flasks having a pre-warmed release medium by using a 21Gneedle. The release medium was 250 ml phosphate buffer pH=7.4. Theflasks were then placed into an oven at 37° C. and kept under horizontalshaking at 50 rpm. At previously scheduled time points (2 h, 1 d, andperiodically up to 42 d), 5 ml of release medium was collected andreplaced with fresh buffer and the amount of risperidone present in thesample was determined by UV spectrophotometry. The profile ofrisperidone released from the implants of this example is shown in FIG.36. The results are expressed as % drug released from implants as afunction of time.

As depicted in FIG. 36, the release of the risperidone is bettercontrolled when DMSO was used as solvent rather than dioxane: Theinitial release is lower in the case of DMSO, and very significantdifferences among the solvents tested were observed during first 7 days.When DMSO is used, the formulation is capable of retaining a sustainabledrug diffusion during at least 14 days. On the other hand, a continuousdrug diffusion was observed when dioxane was used, thus resulting infaster releases and lower duration time periods for the possibletherapeutic effect. This fact reveals that the water miscibility is notthe only characteristic of the solvent to take into account in order todesign and develop injectable in situ implantable formulations. The useof high polar solvents (DMSO) instead of lower ones (Dioxane) induces afaster implant hardening and thus originating a lower drug diffusionduring implant formation.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The risperidone compositions B and C of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone, andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. The total number of rabbits per compositionwas 3. After injection, plasma levels were obtained at 0, 4 h, 1 d, 2 d,5 d, 7 d, 10 d and periodically up to 35 days.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 37. The resultsare expressed as the sum of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As it can be observed in this Figure, the injection of anamount of composition equivalent to 15 mg risperidone to New ZealandWhite rabbits resulted in well controlled initial plasma levels (first 3days) when high polar aprotic water miscible solvents having a dipolemoment 3.7-4.5 D and dielectric constant 30-50 is used. This is inaccordance with previously presented results regarding in vitro releaseof both fentanyl and risperidone, where as expected, solvents which showa controlled and sustained in vitro release have the capacity toreproduce the same behavior following in vivo administration, andeliciting initial controlled and sustained plasma levels for at least 21days, thus minimizing the difference between Cmax and Cmin plasmalevels.

Example 13: Use of Different Water-Soluble Solvents Having DifferentPolarities for the Drug Letrozole

In the present example, the composition of the implantable formulationwas as follows:

Polymer Polymer Polymer lactic/ Inherent Solution glycolic ViscosityComponent Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Letrozole 50:50 0.40 NMP 25 50 116.61.08 B Letrozole 50:50 0.40 DMSO 25 50 116.6 1.12

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

In Vitro Release Profile:

The drug released from the formulations of this example was evaluatedaccording to the following procedure: The amount of formulationcorresponding to 3 mg of letrozole was injected from prefilled syringesinto flasks having a pre-warmed release medium by using a 21G needle.The release medium was 250 ml phosphate buffer pH=7.4. The flasks werethen placed into an oven at 37° C. and kept under horizontal shaking at50 rpm. At previously scheduled time points (2 h, 1 d, and periodicallyup to 31 d), 5 ml of release medium was collected and replaced withfresh buffer and the amount of letrozole present in the sample wasdetermined by HPLC-FLD.

The profile of letrozole released from the implants of this example isshown in FIG. 38. The results are expressed as % drug released fromimplants as a function of time.

As it can be observed in the FIG. 38, and in accordance with Examples 14and 15, the release of the letrozole is well controlled when watermiscible solvents having a large dipole moment (3.7-4.5 D) anddielectric constant (30-50) such as NMP and DMSO are used instead oflower polar solvents (Dioxane), the latter showing a faster diffusion tobody liquids and thus a faster hardening of the implant, especiallyduring the initial release, therefore reducing the drug diffusionphenomenon.

Example 14: Study of the Addition of a pH Modifier

The same risperidone implantable formulations were prepared bycompletely dissolving the polymer in the solvent (DMSO) and subsequentlydispersing the drug in the mentioned polymeric solution with theoptional addition of an alkaline agent such magnesium hydroxide.

Amount (mg) Ingredient No Alkaline agent Alkaline agent PLGA polymer 100100 Risperidone 25 25 Dimethyl sulfoxide (solvent) 233.3 233.3 MagnesiumHydroxide — 8.3Polymer corresponds to a 50:50 lactic/glycolic, inherent viscosity 0.40dL/g polymer.In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone compositions of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. The total number of rabbits was 2. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 39. The resultsare expressed as the sum of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As shown in the cited figure, the injection of an amount offormulation corresponding to 15 mg risperidone to New Zealand Whiterabbits resulted in initial plasma levels starting from 4 hpost-administration up to at least 23 days. However, by the use of analkaline agent within the polymer matrix, a more sustained plasma levelsstarting from 4 h post-administration, and an enlargement of the timewhere therapeutic risperidone plasma levels is achieved, up to at least32 days.

Example 15: Study of the Effect of Sterilization by Irradiation

In the present example, the composition of the risperidone implantableformulations was as follows, always maintaining the same amounts ofdrug, polymer and solvent:

Polymer Polymer Polymer Polymer lactic/ Mean Inherent SolutionIrradiation glycolic Mw Viscosity Component Amount (mg) ViscosityFormulation (KGy) ratio (g/mol) (dL/g) Solvent Drug Polymer Solvent (Pa· s) A 0 50:50 27,020 0.20-0.43 DMSO 25 50 116.6 1.62 B 10 50:50 23,8390.20-0.43 DMSO 25 50 116.6 1.30 C 15 50:50 22,182 0.20-0.43 DMSO 25 50116.6 1.00 D 25 50:50 20,991 0.20-0.43 DMSO 25 50 116.6 0.81 E 0 50:5039,708 0.20-0.58 DMSO 25 50 116.6 6.16 F 15 50:50 30,985 0.20-0.50 DMSO25 50 116.6 2.66 G 25 50:50 27,891 0.20-0.50 DMSO 25 50 116.6 1.78

The implantable formulations were prepared by direct reconstitution ofthe contents of 2 prefilled syringes, a first one with a mixture ofpolymer and risperidone, and a second one with the solvent. The syringeswere connected.

The syringe containing polymer plus risperidone mixtures was sterilizedby 3-irradiation in the range 5-25 KGy. As shown in the table, twodifferent polymers were tested, one being a 50:50 polymer with mean Mw27,020 g/mol, either non-irradiated or irradiated at 10, 15 or 25 Kgy(Formulations A-D), and the other one being a polymer with mean Mw39,708 g/mol, either non-irradiated or irradiated at 15 or 25 Kgy(Formulations E-G).

Formulations A and E received sterilization irradiations evokingdifferent compositions due to the losses in polymer molecular weightduring the process. However, the resulting inherent viscosity was neverbelow 0.20 dL/g in any case, and the polymer solution viscosity wasmaintained between the range 0.26-6.77 Pa·s, which range was previouslystudied and found adequate for this kind of long lasting implantableformulations (Example 9).

In Vitro Release Profile:

The drug released from compositions of this example was evaluatedaccording to the following procedure: The amount of formulationcorresponding to 25 mg of risperidone was injected from prefilledsyringes into flasks having a pre-warmed release medium by using a 21Gneedle. The release medium was 250 ml phosphate buffer pH=7.4. Theflasks were then placed into an oven at 37° C. and kept under horizontalshaking at 50 rpm. At previously scheduled time points (2 h, 1 d, andperiodically up to 28 days), 5 ml of release medium was collected andreplaced with fresh buffer and the amount of risperidone present in thesample was determined by UV spectrophotometry. The profile ofrisperidone released from the implants of this example is shown in FIG.40 and FIG. 41. The results are expressed as % drug released fromimplants as a function of time.

As depicted in FIG. 40, the release of the risperidone from the sameformulation either non irradiated (composition A) or irradiated atdifferent levels (compositions B, C and D) in the range 5-25 KGyresulted in very similar profiles because the inherent viscosity of thepolymer and the viscosity of the polymer solution were still within thepreferred range of 0.20-0.50 dL/g and 0.20 to 7 Pa·s, respectively. FIG.41 shows how the other polymer with a higher Mw (39,708 g/mol)(composition E) which presents an slightly slower release profile, onceit is irradiated (compositions F and G) presents a release profilecloser to the non-irradiated lower Mw polymer (composition A), due tothe loss of molecular weight during sterilization process, which leadsto a composition with a polymer inherent viscosity and polymer solutionviscosity inside preferred ranges.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit:

The risperidone compositions A, B, C, D and G of this example wereinjected intramuscularly to New Zealand White rabbits weighing anaverage of 3 kg. The amount injected corresponded to a dose of 15 mgrisperidone, and the composition was placed intramuscularly in the lefthind leg using a syringe with a 20G needle. The total number of rabbitsper composition was 3. After injection, plasma levels were obtained at0, 4 h, 1 d, 2 d, 5 d, 7 d, 10 d and periodically up to 28 days.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 42 and FIG. 43.The results are expressed as the sum of the risperidone plus9-OH-risperidone concentrations (ng/ml) as a function of time, since thetherapeutic activity of 9-OH-risperidone is substantially equivalent tothat of risperidone. As it can be observed in these Figures, theinjection of an amount of composition equivalent to 15 mg risperidone toNew Zealand White rabbits resulted on very similar plasma levels ascould be predicted since in vitro behavior was very similar afterirradiation. FIGS. 42 and 43 revealed not substantial changes in theplasma levels of the risperidone active moiety when a formulationcomprising 27,020 g/mol mean molecular weight polymer was irradiated at10, 15 and 25 KGy, because key parameters such as the inherent viscosityof the polymer and the viscosity of the polymeric solution viscosity arestill within the previously determined preferred range of 0.20-0.50 dL/gand 0.20 to 7 Pa·s, respectively.

A higher molecular weight polymer (39,708 g/mol), with inherentviscosity out of the preferable range (0.58 dL/g), once it is irradiatedat 25 KGy (since higher molecular weight polymers sufferedproportionally higher molecular weight losses during irradiation), ledto a polymer with inherent viscosity within the preferred range and anstill adequate viscosity of the polymer solution of 1.78 dL/g. Thehigher molecular weight polymer after 25 KGy irradiation resultedextremely close to the non-irradiated lower one (27,020 g/mol), therebyallowing adequate long lasting implantable systems, and experimenting avery similar in vivo behavior (plasma levels profile) as observed inFIG. 43.

Example 16: Study of Reconstitution of the Formulations

Risperidone implantable formulations were prepared with the followingcomposition:

Component Amount (mg) PLGA polymer 50 Risperidone 25 Dimethyl sulfoxide116.7 (solvent)

Polymer corresponds to a 50:50 lactic/glycolic, inherent viscosity 0.40dL/g polymer. The risperidone selected for the compositions of thisexample showed a usual particle size distribution between 10-225 microns(not more than 10% of drug particles with a particle size smaller than10 microns, and not more than 10% larger than 225 microns). Threedifferent methods were applied to reconstitute the composition:

A) Vial. The polymeric solution was prepared by weighing the appropriateamounts of polymer and solvent and mixing them by vortexing until thepolymer had completely dissolved in the solvent. Then, the appropriaterisperidone amount was added to the polymeric solution and anhomogeneous suspension was obtained by vortexing.

B) Syringes. The risperidone, the polymer and the solvent were weighedindependently in glass syringes. The polymeric solution was thenprepared by connecting the respective syringes by a fluid connector sothat the solvent was moved from the syringe containing it to the syringecontaining the polymer and then making several forward-backward cyclesfrom one syringe to the other by pushing the respective plungers. Oncethe polymer is completely dissolved in the solvent, the third syringecontaining the risperidone was connected and an homogeneous suspensionwas then obtained by doing several additional cycles.

C) Freeze-drying. Polymer and risperidone were freeze-dried in aprefilled glass syringe and the solvent was placed in a second syringe.The syringes were connected by a fluid connector and then the solventwas moved to the syringe containing the freeze-dried polymer-risperidonemixture and finally several forward-backward cycles were repeated untila homogeneous suspension was achieved.

Preparation methods B and C can also be carried out by direct connectionof syringes using female-male luer syringes.

In Vitro Release Profile:

The risperidone released from formulations corresponding to the 3methods was evaluated according to the following procedure: the amountof formulation corresponding to 25 mg of risperidone was injected fromprefilled syringes into flasks by using a 21G needle followed by thecareful addition of a pre-warmed release medium. The release medium was250 ml phosphate buffer pH=7.4. The flasks were then placed into an ovenat 37° C. and kept under horizontal shaking at 50 rpm. At previouslyscheduled time (2 h, 1 d, 3 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d,31 d and 35 d), 5 ml of release medium was collected and replaced withfresh buffer, and the amount of risperidone amount present in the samplewas determined by UV spectrophotometry.

The profile of risperidone released from the implants is shown in FIG.44. The results are expressed as % Risperidone released from theformulation as a function of time. As it can be observed in FIG. 44, therelease profile of the implantable formulations prepared by the threedifferent methods was the same during first 2 weeks. However, after 14days the preparation method A (vial) resulted in a slightly slowerrelease rate, probably due the higher porosity of the implants formed bythe other 2 methods because of the air introduced to the formulationduring the reconstitution process.

In Vivo Plasma Levels after Intramuscular Administration to New ZealandRabbit

The risperidone compositions of this example were injectedintramuscularly to New Zealand White rabbits weighing an average of 3kg. The amount injected corresponded to a dose of 15 mg risperidone andthe composition was placed intramuscularly in the left hind leg using asyringe with a 20G needle. The total number of rabbits was 2. Afterinjection, plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 45. The resultsare expressed as the sum of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As it can be seen in the cited Figure, the injection of anamount of formulation corresponding to 15 mg risperidone to New ZealandWhite rabbits resulted in initial plasma levels starting from 4 hpost-administration up to at least 28 days. The methods consisting onreconstitution of a formulation pre-filled in different containers bytheir mixing (Methods B and C) evoked slightly higher initial plasmalevels. This could be due to the higher porosity, and consequentlyhigher initial diffusion, of the implantable formulations prepared bythese two methods in comparison with Method A (preparation inside avial). This fact could be also the reason for their higher plasma levelsduring the first week after administration.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog

The risperidone formulations of this example were also injectedintramuscularly to Beagle dogs weighing an average of 10 kg. The amountinjected corresponded to a dose of 25 mg risperidone and the compositionwas placed intramuscularly in the left hind leg using a syringe with a20G needle. Total number of dogs was 3. After injection, plasma levelswere obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21d, 24 d, 28 d, 31 d, 35 d, 38 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of therisperidone active moiety plasma levels is shown in FIG. 46. The resultsare expressed as the sum of the risperidone plus 9-OH-risperidoneconcentrations (ng/ml) as a function of time, since the therapeuticactivity of 9-OH-risperidone is substantially equivalent to that ofrisperidone. As it can be seen in the cited Figure, the injection of anamount of formulation corresponding to 25 mg risperidone to Beagle dogsresulted in well-controlled initial plasma levels with sustained andsimilar levels up to at least 35 days using different preparationmethods such as prior elaboration of polymeric solution followed by drugaddition (vial, method A) or by direct reconstitution starting fromsolid components (syringes, method B).

The above experiments clearly demonstrate that, in an injectable depotcomposition intended to release a drug contained therein, the initialburst release of the drug can be satisfactorily controlled bycontrolling at least one of the following factors:

-   -   the viscosity of the polymeric solution;    -   the intrinsic or inherent viscosity (η_(inh)) of the polymer;        and    -   the water solubility of the drug.

By adequately controlling at least one of these factors, the release ofthe drug from the implant can be precisely controlled during at leastthe first 14 days and up to 6 months following a single administration.The injectable compositions of the invention can therefore form asuspension/dissolution/dispersion within a biodegradable andbiocompatible polymeric solution that can be parenterally administeredfor example by means of a syringe and a needle and which solidifiesinside the body by solvent diffusion, thereby forming the implant.

As used herein, the term about is taken to mean±10%, 5% or 1% of aspecified value.

ADDITIONAL DISCLOSURE

Risperidone is an atypical antipsychotic drug with benzisoxazole andpiperidine functional groups. It acts as a strong dopaminergicantagonist and selective serotonin receptor antagonist. Risperidone isFDA approved for the treatment of schizophrenia since 1993. It is theonly drug presently approved for the treatment of schizophrenia in youngpeople under 18 years, and together with lithium, for the treatment ofbipolar disorders in children/youth ages between 10-18 years old.

Another aspect of the invention provides the use of an injectable depotcomposition as described herein for the treatment of schizophrenia orbipolar disorders in the human body. The method comprises administeringto a subject in need thereof an amount of injectable depot compositionas described herein sufficient to provide a therapeutic dose ofrisperidone for a period of at least two weeks following administrationthereof.

Embodiments of the invention include those wherein: a) the compositionis administered every two weeks, every three weeks, every four weeks orevery five weeks during a treatment period; b) the composition providesa therapeutic plasma level of risperidone or other form thereof fromwithin 24 hours after administration to at least 14 days afteradministration; c) the plasma level of active moiety ranges from about 5to about 150 ng/ml and preferably from about 10 to about 100 ng/ml inthe steady state during a dosing period; d) the implant provides anactive moiety (risperidone+9-OH risperidone) plasma level within therange of about 5 to about 80 ng/ml when about 116 to about 700 mg,respectively, of the composition comprising about 25 to about 150 mg,respectively, of risperidone are administered via injection; e) theinjectable composition is exposed to an aqueous fluid thereby forming asolid body which is then administered to a subject in need thereof; f)the injectable composition is formed within one month, within threeweeks, within two weeks, within one week, within three days, within oneday, within less than one day, within 18 hours, within 12 hours, within6 hours, within 1 hour, within 15 minutes or within 5 minutes prior toadministration to a subject; g) the injectable composition is warmed orcooled prior to administration to a subject; h) the polymer, solvent,polymer solution and/or drug is sterilized prior to administration; i)sterilization comprises sterilization of the drug or polymer by exposureto beta-irradiation in the range 5-25 KGy; j) sterilization comprisessterilization of the polymer solution by filtration through a filtrationmedium having a nominal pore size of 22 microns or less; and/or k) thecomposition is administered intramuscularly, intraperitoneally,intrathecally, intravaginally, subcutaneously, intracranially orintracerebrally. In some embodiments, the preferred mode ofadministration is intramuscular.

The injectable composition is used to treat a disorder, disease orcondition that is therapeutically responsive to risperidone. Theinvention comprises administering to a subject in need thereof an amountof injectable composition sufficient to provide therapeutic plasmalevels of risperidone in the subject during the period of at least 1 to14, at least 2 to 14 or at least 3 to 14 days after administration (thedosing period). The dosing period can exceed two weeks.

Additional parameters such as the mass ratio between the amounts ofpolymeric solution (polymer+solvent) and drug, and the solvent/drug massratio, can also be useful to provide control over the initial release ofrisperidone from the compositions of the invention.

A first aspect of the invention provides an injectable depotcomposition, comprising:

-   a drug, such as is risperidone and/or its metabolites or prodrugs in    any combination thereof;-   at least a biocompatible polymer which is a copolymer comprising    lactic acid and glycolic acid monomers, wherein the monomers are    present at a monomer ratio of lactic to glycolic acid in the range    from about 48:52 to about 77:23., and-   at least a water-miscible solvent with a dipole moment about 3.9-4.3    D,-   wherein the solvent and polymer form a polymer solution having a    viscosity in the range of 0.5 to 3.0 Pa·s, and the solvent/drug mass    ratio ranges from about 10:1 to about 4:1,-   characterised in that the drug/polymer mass ratio is between 25 and    35% expressed as the weight percentage of the drug with respect of    the drug plus polymer.

In some embodiments, the concentration of the polymeric component in theinjectable composition is in the range of about 25-50%, (expressed asthe percentage of polymer weight based on total polymeric solutioncomponent) and or about 30-40%.

In some embodiments, the injectable composition has a viscosity in therange of about 0.5-7.0 Pa·s, more preferably about 0.5-3.0 Pa·s, andmost preferably about 0.7-3.0 Pa·s.

In some embodiments, the compositions of the invention comprise abiodegradable poly(L-lactide-co-glycolide) copolymer (PLGA) matrix. Themonomer ratio of lactic acid to glycolic acid monomers present in thepolymer can range from about 45:65 to about 75:25, about 50:50 to about75:25, about 50:50 to about 70:30, about 50:50 to about 65:35, or about65:35 to about 75:25. In some embodiments, the intrinsic or inherentviscosity of the polymer is in the range of about 0.16 to about 0.60dl/g when measured in chloroform at 25° C. and a 0.1% (wt/v)concentration. In some embodiments, the PLGA copolymer is end-capped. Insome embodiments, the PLGA copolymer is irradiated with beta-radiationprior to inclusion in the injectable composition. In some embodiments, acommercially available PLGA copolymer has an initial intrinsic viscositythat is to high for use but after irradiation with beta-radiation it hasan intrinsic viscosity that is within the ranges specified hereinthereby rendering it suitable for use in the injectable composition.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   a polymeric solution comprising a biodegradable    poly(L-lactide-co-glycolide) polymer having a monomer ratio of    lactic acid to glycolic acid in the range of 50:50 to 75:25, and a    solvent having a dipole moment in the range of 3.9-4.3 D, wherein    the solvent is present in an amount sufficient to dissolve the    polymer; and-   drug-containing particles of risperidone, a metabolite of    risperidone, a prodrug of risperidone or a combination thereof at    least partially dispersed in the polymeric solution, the particles    having a size distribution as follows: not more than 10% of the    total volume of drug particles is less than 10 microns in size, not    more than 10% of the total volume of drug particles is greater than    225 microns in size, and the d0.5 of the size distribution is in the    range of about 60-130 microns; wherein-   the intrinsic or inherent viscosity of the polymer is in the range    of about 0.16 to about 0.60 dl/g when measured in chloroform at    25° C. and a 0.1% concentration;-   the viscosity of the polymeric solution is in the range of about    0.5-7.0 Pa·s;-   the concentration of drug in the injectable composition is in the    range of about 4 and 16 wt %, expressed as the percentage of the    drug with respect to the total composition weight, or the mass ratio    of the amount of polymeric solution (polymer+solvent) to the amount    of drug in the injectable composition ranges from about 15:1 to 5:1;-   the concentration of polymer in the injectable composition is in the    range of about 25-50% expressed as the percentage of polymer weight    based on total polymeric solution component; and-   the composition has a solvent/drug mass ratio ranging from about    10:1 to about 4:1.

Embodiments of the invention include those wherein: a) the risperidoneis present in solid form in the container prior to mixing with thesolvent; b) the risperidone is present in particulate form or as alyophilisate in the container prior to mixing with the solvent; c) theparticle size distribution of the risperidone is as follows: not morethan 10% of the total volume of drug particles are less than 10 micronsin size and not more than 10% of the total volume of drug particles aregreater than 225 microns in size; d) the d0.5 of the particle sizedistribution is in the range of about 60-130 microns; e) the mass ratioof the amount of polymeric solution (polymer+solvent) and to the amountof risperidone in the injectable composition ranges from about 15:1 to5:1; f) the mass ratio of the amount of solvent and the amount ofrisperidone (mg solvent/mg risperidone) in the injectable compositionranges from about 12:1 to 4:1; g) the kit further comprises an alkalineagent; h) the mole ratio of risperidone to alkaline agent ranges from2/3 to 2/5; i) the solvent, polymeric solution, risperidone and/orinjectable composition is sterilized prior to administration; and/or j)the kit further comprises an alkaline agent in either or bothcontainers.

In some embodiments, the invention provides a process for preparing aninjectable composition, comprising: a) dissolving a polymer having amolecular weight greater than about 15 KDa in a solvent having a dipolemoment about 3.9-4.3 D to form a polymeric solution having a viscositygreater than about 0.5 Pa·s, wherein the concentration of the polymer inthe solution is in the range of about 25-50%, expressed as thepercentage of polymer weight based on total solution weight, wherein thepolymer comprises lactic acid and glycolic acid monomers, wherein themonomers are present at a monomer ratio of lactic acid to glycolic acidin the range of about 50:50 to 75:25; and b) subjecting the polymer toat least 10 KGy of β-irradiation to degrade at least a portion of thepolymer thereby reducing its molecular weight to a range of about 25-52KDa and reducing the viscosity of a respective polymeric solutionthereof to a range of about 0.5 to 3.0 Pa·s. In some embodiments, drugis included in the polymeric solution, and the weight percentage of drugwith respect to the total weight of drug plus polymer is in the range ofabout 25 to 35%.

Another factor contributing to controlling the initial release of drugfrom the implant is the risperidone/polymer mass ratio of the injectablecomposition. In some embodiments, this mass ratio, expressed as thepercentage of the drug weight with respect to total weight of the drugplus polymer, is in the range of about 15-40% weight, more preferablyabout 25-35% wt, and most preferably about 33% wt.

In some embodiments, the mass ratio of the amount of polymeric solution(polymer+solvent) to the amount of risperidone in the injectablecomposition ranges from about 15:1 to 5:1, more preferably from about12:1 to 5:1 and most preferably from about 7:1 to 6.5:1. In the mostpreferred embodiments, this mass ratio is about 6.66:1.

In some embodiments, the mass ratio of the amount of solvent and theamount of risperidone (mg solvent/mg risperidone) in the injectablecomposition ranges from about 12:1 to 4:1, more preferably about 10:1 to4:1 and most preferably about 5:1 to 4:1. In the most preferredembodiments, this mass ratio is about 4.66:1.

The invention also provides an injectable composition that forms asingle solid body implant in a subject to which it is administered, thecomposition comprising:

-   a polymeric solution comprising a biodegradable    poly(L-lactide-co-glycolide) polymer having a monomer ratio of    lactic acid to glycolic acid in the range of 50:50 to 75:25, and a    solvent having a dipole moment in the range of 3.9-4.3 D; and-   drug-containing particles of risperidone, a metabolite of    risperidone, a prodrug of risperidone or a combination thereof    dispersed in the polymeric solution, the particles having a size    distribution as follows: not more than 10% of the total volume of    drug particles is less than 10 microns in size, not more than 10% of    the total volume of drug particles is greater than 225 microns in    size, and the d0.5 of the size distribution being in the range of    about 60-130 microns; wherein-   the composition has a solvent/drug mass ratio ranging from about    10:1 to about 4:1.

Yet another factor contributing to controlling the initial release ofdrug from the implant is the drug's particle size. Large particlesprovide a smaller surface area per weight thereby reducing the initialrelease (burst) but the release may be then delayed until the beginningof the degradation of the polymeric matrix. On the other hand, smallparticles evoke higher burst levels due to increased surface area andeasier drug diffusion from small particles during implant hardening,followed by continuous drug release levels due to the combination of theprocesses of drug diffusion and implant erosion. Consequently, in apreferred embodiment of the invention a wide particle size distribution,combining large and small particle sizes in different ratios, is used inorder to reduce the initial burst and still maintain a suitable constantdrug release by diffusion of smaller particles during the first phase ofrelease and gradual release of drug from the bigger particles while thepolymer degrades, i.e. during the period of time (days to weeks)following the initial burst phase. In some embodiments, the particlesize distribution of the drug is as follows: not more than 10% of thetotal volume of drug particles are less than 10 microns in size(equivalent diameter in volume as a function of applying Fraunhofertheory to irregularly shape particles; as measured by laser lightscattering, such as with a Malvern Mastersizer 2000) and not more than10% of the total volume of drug particles are greater than 225 micronsin size. In addition, the drug particles possess a d0.5 value preferablyin the range of about 60-130 microns. Accordingly, in some embodiments,the risperidone comprises a broad particle size distribution, which canbe monomodal, bimodal or trimodal.

The risperidone-implantable formulations were prepared by completelydissolving the polymer in the solvent and subsequently suspending thedrug in said polymeric solution. The following different risperidoneparticle size distributions were evaluated for the same formulation:

-   -   25-350 microns: d0.1, 25 microns and d0.9, 350 microns (not more        than 10% of drug particles with a particle size smaller than 25        microns, and not more than 10% particles larger than 350        microns)    -   25-225 microns: d0.1 of 25 microns and d0.9 of 225 microns (not        more than 10% of drug particles with a particle size smaller        than 25 microns, and not more than 10% particles larger than 225        microns)    -   90-150 microns: sieved between 90-150 microns    -   45-90 microns: sieved between 45-90 microns    -   milled, <10 microns: drug milled to d0.9 10 microns (not more        than 10% particles larger than 10 microns).

The profile of risperidone released from the implants of this exampleare expressed as % Risperidone released from the implants as a functionof time. The small drug particles (less than 10 microns) favoured the invitro drug diffusion during the first few days following administrationof the implantable formulation, whereas the use of a mixture of particlesizes, comprising larger and smaller particles, reduced the initialdiffusion. Accordingly, in some embodiments, the risperidone comprises abroad particle size distribution, which can be monomodal, bimodal ortrimodal.

The compositions of the invention comprise at least a polymer or polymermatrix, a solvent and a drug. The polymer is preferably a biocompatibleand biodegradable polymer or polymer matrix. In order not to causesevere damage to the body following administration, the preferredpolymers are biocompatible, non-toxic for the human body, notcarcinogenic, and do not induce significant tissue inflammation. Thepolymers are preferably biodegradable in order to allow naturaldegradation by body processes, so that they are readily disposable anddo not accumulate in the body. In selecting the appropriate grade ofPLGA copolymer, the time required for degradation of PLGA is related tothe monomer ratio used in production: the higher the content ofglycolide units, the lower the time required for degradation. Inaddition, polymers that are end-capped with esters (as opposed to thefree carboxylic acid) demonstrate longer degradation half-lives. Thepreferred polymers are selected from end-capped terminal carboxylicpoly-lactide and poly-glycolic acid copolymers (PLGA) mixed in a ratiofrom 50:50 to 75:25 (ratio of lactic acid monomer to glycolic acidmonomer), with an intrinsic or inherent viscosity preferably in therange of 0.16-0.60 dl/g, and more preferably between 0.25-0.48 dl/g, asmeasured in chloroform at 25° C. and at a concentration of 0.1% wt/vwith a Ubbelohde size 0c glass capillary viscometer (RESOMER® grades) oras measured in chloroform at 30° C. and at a concentration of 0.5% wt/vwith a size 25 Cannon-Fenske glass capillary viscometer (LAKESHOREMATERIALS™ grades). In some embodiments, the PLGA copolymer has a lacticacid to glycolic acid monomer ratio ranging from 48:52 to 52:48 or 48:52to 77:23 or 45:55 to 55:45 or about 50:50 or 50:50±10%.

As used herein, the term “polymeric solution” is taken to mean the fluidcomposition comprising a combination of the solvent and the polymerdissolved therein. In some embodiments, at least 80%, at least 90%, atleast 95%, at least 99% or all of the polymer is dissolved in thesolvent. If not otherwise specified, the viscosity value of thepolymeric solution or the injectable composition is given in Pa·s units,measured in chloroform at 25° C. and at concentration of 0.1% wt/v.

In some embodiments, the drug is completely dissolved, partiallydissolved or completely undissolved in the solvent used to form thepolymeric solution to form the injectable composition. The drug ispreferably at least partly suspended, i.e. only partially dissolved, inthe solvent or polymeric solution. In some embodiments, ≤5%, ≤10%, ≤20%,≤30%, ≤40%, ≤50%, ≤60%, ≤70%, ≤80%, ≤90%, ≤95% or ≤99% wt of the drug isdissolved in the solvent or polymeric solution to form the injectablecomposition. In some embodiments, ≥1%, ≥5%, ≥10%, ≥20%, ≥30%, ≥40%,≥50%, ≥60%, ≥70% or up to about 80% wt. of the drug is dissolved in thesolvent or polymeric solution to form the injectable composition.

In some embodiments, the concentration of drug in the injectablecomposition is generally in the range of about 4 and 16 wt %, expressedas the percentage of the drug with respect to the total compositionweight. More preferably, the drug content is between 7 and 15% wt, andmost preferably about 13% wt with respect to the total compositionweight.

One of the factors contributing to controlling the initial release ofdrug from the implant, after placement in an aqueous environment, is theviscosity of the polymeric solution of the injectable composition. Theterm “polymeric solution” is defined as the combination of the polymermatrix and the solvent in which it is dissolved. In some embodiments,the polymeric solution has a viscosity in the range of about 0.5-7.0Pa·s, more preferably about 0.5-3.0 Pa·s, and most preferably about0.7-3.0 Pa·s.

Another factor contributing to controlling the initial release of drugfrom the implant is the risperidone/polymer mass ratio of the injectablecomposition. In some embodiments, this mass ratio, expressed as thepercentage of the drug weight with respect to total weight of the drugplus polymer, is in the range of about 15-40% weight, more preferablyabout 25-35% wt, and most preferably about 33% wt.

The plasma concentration profile during the dosing period can exhibitone, two, or more maxima and one, two or more minima. An initial maximumcan be caused by dissolution of risperidone during the initial day(s) ofthe dosing period followed by a slowing of the release thereof andanother maximum can be caused by increased rate of release during theremaining days of the dosing period. Embodiments of the inventioninclude those wherein: a) the plasma profile exhibits a maximum duringthe initial one to three days or one to two days of the dosing period;b) the plasma profile exhibits a maximum during the latter 11 to 13 daysor 12 to 14 days of the dosing period; c) the plasma profile exhibits amaximum during the initial days of the dosing period and a maximumduring the remaining days of the dosing period; or d) the plasma profileis substantially level (within ±20%, ±15%, ±10% or ±5% of the average ormean) during the dosing period.

Embodiments of the invention include those wherein: a) the molecularweight of the polymer is greater before irradiation than it is afterirradiation; b) the molecular weight of the polymer is greater than 15KDa before irradiation; c) the molecular weight of the polymer is in therange of 15-60 KDa, 25-52 KDa or 28-43 KDa after irradiation; d) theviscosity of a polymeric solution containing polymer that has not beenirradiated is greater than about 0.5 Pa·s; e) the viscosity of apolymeric solution containing polymer that has been irradiated is in therange of 0.5-7.0 Pa·s, 0.5-3.0 Pa·s or 0.7 to 2.0 Pa·s.; and/or f) thesufficient amount of radiation is at least 10, at least 15, at least 20or at least 25 KGy.

1) A method of administering drug, which is risperidone, paliperidone, or a combination thereof, to a subject, said method comprising a) mixing the contents of two or more containers to provide an injectable depot composition; and b) administering to said subject said injectable composition, wherein said injectable depot composition consists of said drug, and a polymeric solution of DMSO and PLGA copolymer, and wherein: the content of said drug is 13% wt±10%, based upon the weight of the composition, and said drug possesses a particle distribution selected from: a. not more than 10% of the total volume of the particles is smaller than 10 microns, not more than 10% of the total volume of particles is greater than 225 microns, and the d0.5 is in the range of 10-200 microns; b. not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm; or c. expressed as volume, d0.9 is about 150 to about 400 μm, d0.5 is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm; the mass ratio of DMSO to drug is 4.66±10%:1; the mass ratio of polymeric solution to drug is 6.66±10%:1; the PLGA copolymer is an end-capped biodegradable poly(lactide-co-glycolide) copolymer having a monomer ratio of lactic acid to glycolic acid of 50:50±10% and an inherent viscosity in the range of 0.20±10% dl/g to 0.50±10% dl/g as measured in chloroform at 25° C. at a concentration of 0.1% wt/v with an Ubbelohde size 0c glass capillary viscometer; the polymeric solution has a viscosity in the range of 0.5-3.0 Pa·s±10%; and the amount of said drug dissolved in the injectable composition is ≤20% wt. 2) The method of claim 1, wherein said composition is administered intramuscularly, intraperitoneally, intrathecally, intravaginally, subcutaneously, intracranially or intracerebrally 3) The method of claim 1, wherein said composition is administered to the subject every four weeks, every five weeks, every six weeks, every two months, every three months, every four months, every five months, or every six months. 4) The method of claim 1, wherein after administration said composition provides measurable plasma levels of said drug from within 1 day after administration throughout a dosing period of at least four weeks following administration thereof. 5) The method of claim 1, wherein after administration said composition provides a drug total plasma level within the range of about 5 ng/ml to about 80 ng/ml when about 116 mg to about 700 mg, respectively, of the composition comprising about 25 mg to about 150 mg, respectively, of said drug is administered to the subject. 6) The method of claim 1, wherein after administration said composition provides a pharmacokinetic plasma profile, for said drug, defined as follows Dose (mg) Cmin (ng/ml) Cavg (ng/ml) Cmax (ng/ml) 25-150 1-80 3-200 8-300

during a dosing period of at least 14 days following administration to the subject of an amount of the composition equivalent to the dose indicated. 7) The method of claim 1, wherein after administration a) said composition provides a satisfactorily controlled release profile, for said drug, throughout a dosing period of at least 21 days after administration, whereby the composition releases about 0.5% to no more than about 12% of its dose of said drug within 24 hours after administration; b) said composition provides a substantially level plasma profile, for said drug, of within ±15% of the average or mean during a period of at least 14 days following administration of the composition to a subject, wherein the average or mean is calculated over the 14 days; c) said composition provides a substantially level plasma profile, for said drug, of within ±10% of the average or mean during a period of at least 14 days following administration of the composition to a subject, wherein the average or mean is calculated over the 14 days; or d) said composition provides a substantially level plasma profile, for said drug, of within ±20% of the average or mean during a period of at least 28 days following administration of the composition to a subject, wherein the average or mean is calculated over the 28 days. 8) The method of claim 1, wherein after administration an implant formed from said composition releases a) about 0.5% to no more than about 12% of its dose of said drug within 24 hours after administration to said subject; or b) about 0.5% to no more than about 8% of its dose of said drug within 24 hours after administration to said subject. 9) The method of claim 1 further comprising sterilizing said composition. 10) The method of claim 1 further comprising sterilizing said PLGA copolymer prior to inclusion in said composition or prior to mixing with said DMSO. 11) The method of claim 1 further comprising irradiating at least one of said drug and said PLGA copolymer with beta-irradiation in the range of 5-25 KGy. 12) The method of claim 11, wherein the beta-irradiation is sufficient to reduce the molecular weight and intrinsic viscosity of the PLGA copolymer. 13) The method of claim 1, wherein said injectable composition has a viscosity is in the range of about 0.7 Pa·s to about 4.0 Pa·s. 14) The method of claim 1 further comprising providing a kit for preparing said injectable composition, wherein said kit comprises at least a first container comprising the PLGA copolymer; and at least a second container comprising the DMSO, wherein said drug is present in the first container, the second container or a third container. 15) The method of claim 14, wherein said kit comprises about 25 to about 150 mg of said drug. 16) The method of claim 14, wherein one or more of said containers is a syringe, vial or cartridge. 17) The method of claim 14, wherein at least one of said drug and said PLGA copolymer is present in solid form prior to mixing with the DMSO. 18) The method of claim 17, wherein said drug and said PLGA copolymer are present in the same container prior to mixing with the DMSO. 19) The method of claim 1 further comprising filtering at least one of said DMSO and said polymeric solution. 20) The method of claim 1 further comprising cooling or warming said composition prior to said administering. 21) A method of administering drug, which is risperidone, paliperidone, or a combination thereof, to a subject, said method comprising a) mixing the contents of two or more containers to provide an injectable depot composition; and b) administering to said subject said injectable composition, wherein said injectable depot composition consists of said drug, and a polymeric solution of DMSO and PLGA copolymer, and wherein: the content of said drug is 13% wt±10%, based upon the weight of the composition, and said drug possesses a particle distribution selected from: a) not more than 10% of the total volume of the particles is smaller than 10 microns, not more than 10% of the total volume of particles is greater than 225 microns, and the d0.5 is in the range of 10-200 microns; b) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm; or c) expressed as volume, d0.9 is about 150 to about 400 μm, d0.5 is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm; the mass ratio of DMSO to drug is 4.66±10%:1; the mass ratio of polymeric solution to drug is about 6.66±10%:1; the PLGA copolymer is an end-capped biodegradable poly(lactide-co-glycolide) copolymer having a monomer ratio of lactic acid to glycolic acid of 50:50±10% and an inherent viscosity in the range of 0.20±10% dl/g to 0.50±10% dl/g as measured in chloroform at 25° C. at a concentration of 0.1% wt/v with an Ubbelohde size 0c glass capillary viscometer; the polymeric solution has a viscosity in the range of 0.5-3.0 Pa·s±10%; the amount of said drug dissolved in the injectable composition is 20% wt; at least one of said drug and PLGA copolymer has been irradiated with beta-irradiation in the range of 5-25 KGy; and the viscosity of the composition is in the range of 0.7-4.0 Pa·s±10%. 22) The method of claim 21, wherein said injectable composition comprises 25-150 mg of said drug. 23) The method of claim 21 further comprising providing a kit for preparing said composition, wherein said kit comprises at least a first container comprising the PLGA copolymer; and at least a second container comprising the DMSO, wherein said drug is present in the first container, the second container, or a third container. 